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| COVID-19 research v1.52 | IFNG |
Sarah Leigh changed review comment from: IFNG was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility). "Illumina review: From OMIM: Interferon-gamma (IFNG), or type II interferon, is a cytokine critical for innate and adaptive immunity against viral and intracellular bacterial infections and for tumor control. The importance of IFNG in the immune system stems in part from its ability to inhibit viral replication directly, but most importantly derives from its immunostimulatory and immunomodulatory effects. IFNG is produced predominantly by natural killer (NK) and natural killer T (NKT) cells as part of the innate immune response, and by CD4 (186940) and CD8 (see 186910) cytotoxic T lymphocyte (CTL) effector T cells once antigen-specific immunity develops (PMID: 178981204; Schoenborn and Wilson, 2007). From OMIM: PMID: 17215375: Huang et al. (2007) The IFNG gene SNP, -764 C>G (rs2069707) in the proximal promoter region next to the binding motif for HSF1 , was significantly associated with sustained virologic response to IFNA therapy in a cohort of hepatitis C virus-positive patients compared to a cohorts who had spontaneously cleared HCV infection or who had chronic HCV infection. Luciferase reporter and EMSA analyses showed that the -764G allele had 2- to 3-fold higher promoter activity and stronger binding affinity for HSF1 than the -764C allele. Huang et al. (2007) concluded that the -764C-G SNP is functionally important in determining viral clearance and treatment response in HCV-infected patients. From OMIM PMID: 12854077: An et al. (2003) reported an association between a SNP in the IFNG promoter region, -173 G>T, and progression to AIDS. In individuals with the rare -179T allele, but not in those with the -179G allele, IFNG is inducible by TNF. An et al. (2003) studied 298 African American HIV-1 seroconverters and found that the -179T allele was associated with accelerated progression to a CD4 cell count below 200 and to AIDS. They noted that the SNP is present in 4% of African Americans and in only 0.02% of European Americans. PMID: 26458193 Wei et al. (2017) Eleven independent case-control studies were selected for the meta-analysis, comprising a total of 1527 HBV cases and 1467 healthy subjects. carriers of the IFN-γ A allele were more likely to develop HBV infection than those without in all five genetic models (all p < 0.05). According to the ethnicity-based sub-group analysis, a significant difference of the IFN-γ rs2430561 T > A (IFN-γ +874T/A) polymorphism was detected associated with the increased risk of HBV infection in Asians and European-derived populations in the majority of the groups. ; to: IFNG was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility). Illumina review: From OMIM: Interferon-gamma (IFNG), or type II interferon, is a cytokine critical for innate and adaptive immunity against viral and intracellular bacterial infections and for tumor control. The importance of IFNG in the immune system stems in part from its ability to inhibit viral replication directly, but most importantly derives from its immunostimulatory and immunomodulatory effects. IFNG is produced predominantly by natural killer (NK) and natural killer T (NKT) cells as part of the innate immune response, and by CD4 (186940) and CD8 (see 186910) cytotoxic T lymphocyte (CTL) effector T cells once antigen-specific immunity develops (PMID: 17981204; Schoenborn and Wilson, 2007). From OMIM: PMID: 17215375: Huang et al. (2007) The IFNG gene SNP, -764 C>G (rs2069707) in the proximal promoter region next to the binding motif for HSF1 , was significantly associated with sustained virologic response to IFNA therapy in a cohort of hepatitis C virus-positive patients compared to a cohorts who had spontaneously cleared HCV infection or who had chronic HCV infection. Luciferase reporter and EMSA analyses showed that the -764G allele had 2- to 3-fold higher promoter activity and stronger binding affinity for HSF1 than the -764C allele. Huang et al. (2007) concluded that the -764C-G SNP is functionally important in determining viral clearance and treatment response in HCV-infected patients. From OMIM PMID: 12854077: An et al. (2003) reported an association between a SNP in the IFNG promoter region, -173 G>T, and progression to AIDS. In individuals with the rare -179T allele, but not in those with the -179G allele, IFNG is inducible by TNF. An et al. (2003) studied 298 African American HIV-1 seroconverters and found that the -179T allele was associated with accelerated progression to a CD4 cell count below 200 and to AIDS. They noted that the SNP is present in 4% of African Americans and in only 0.02% of European Americans. PMID: 26458193 Wei et al. (2017) Eleven independent case-control studies were selected for the meta-analysis, comprising a total of 1527 HBV cases and 1467 healthy subjects. carriers of the IFN-γ A allele were more likely to develop HBV infection than those without in all five genetic models (all p < 0.05). According to the ethnicity-based sub-group analysis, a significant difference of the IFN-γ rs2430561 T > A (IFN-γ +874T/A) polymorphism was detected associated with the increased risk of HBV infection in Asians and European-derived populations in the majority of the groups. |
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| COVID-19 research v1.37 | NUP214 |
Sarah Leigh changed review comment from: NUP214 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 1 grouping (clear GDA/viral susceptibility); to: NUP214 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 1 grouping (clear GDA/viral susceptibility). Illumina review: PMID 31178128: Fichtman et al. (2019) reported four patients from two unrelated families with fever-induced, partially reversible acute encephalopathy and regression, progressive microcephaly, and brain atrophy. Febrile episodes were associated with viral infections. Exome sequencing identified that both affected individuals from family A were homozygous for the NUP214 NM_005085.3; c.112C>T (p.Arg38Cys) missense variant. A frameshift variant, c.1574delC (p.Pro525LeufsTer6) and a missense variant c.1159C>T (p.Pro387Ser), found in a compound heterozygous state were identified in the NUP214 gene in the two affected individuals from family B. The missense variants affected highly conserved residues and were present at a low frequency in gnomAD. Functional studies on primary skin fibroblasts derived from one case (family A1) supported pathogenicity of the p.Arg38Cys variant; NUP214 and NUP88 protein levels were reduced in while the total number and density of nuclear pore complexes remained normal. Nuclear transport assays revealed defects in the classical protein import and mRNA export pathways in affected cells. |
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| COVID-19 research v1.30 | IFNG |
Sarah Leigh changed review comment from: IFNG was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility); to: IFNG was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility). "Illumina review: From OMIM: Interferon-gamma (IFNG), or type II interferon, is a cytokine critical for innate and adaptive immunity against viral and intracellular bacterial infections and for tumor control. The importance of IFNG in the immune system stems in part from its ability to inhibit viral replication directly, but most importantly derives from its immunostimulatory and immunomodulatory effects. IFNG is produced predominantly by natural killer (NK) and natural killer T (NKT) cells as part of the innate immune response, and by CD4 (186940) and CD8 (see 186910) cytotoxic T lymphocyte (CTL) effector T cells once antigen-specific immunity develops (PMID: 178981204; Schoenborn and Wilson, 2007). From OMIM: PMID: 17215375: Huang et al. (2007) The IFNG gene SNP, -764 C>G (rs2069707) in the proximal promoter region next to the binding motif for HSF1 , was significantly associated with sustained virologic response to IFNA therapy in a cohort of hepatitis C virus-positive patients compared to a cohorts who had spontaneously cleared HCV infection or who had chronic HCV infection. Luciferase reporter and EMSA analyses showed that the -764G allele had 2- to 3-fold higher promoter activity and stronger binding affinity for HSF1 than the -764C allele. Huang et al. (2007) concluded that the -764C-G SNP is functionally important in determining viral clearance and treatment response in HCV-infected patients. From OMIM PMID: 12854077: An et al. (2003) reported an association between a SNP in the IFNG promoter region, -173 G>T, and progression to AIDS. In individuals with the rare -179T allele, but not in those with the -179G allele, IFNG is inducible by TNF. An et al. (2003) studied 298 African American HIV-1 seroconverters and found that the -179T allele was associated with accelerated progression to a CD4 cell count below 200 and to AIDS. They noted that the SNP is present in 4% of African Americans and in only 0.02% of European Americans. PMID: 26458193 Wei et al. (2017) Eleven independent case-control studies were selected for the meta-analysis, comprising a total of 1527 HBV cases and 1467 healthy subjects. carriers of the IFN-γ A allele were more likely to develop HBV infection than those without in all five genetic models (all p < 0.05). According to the ethnicity-based sub-group analysis, a significant difference of the IFN-γ rs2430561 T > A (IFN-γ +874T/A) polymorphism was detected associated with the increased risk of HBV infection in Asians and European-derived populations in the majority of the groups. |
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| COVID-19 research v1.19 | CPT2 |
Sarah Leigh changed review comment from: CPT2 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 1 grouping (clear GDA/viral susceptibility); to: CPT2 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 1 grouping (clear GDA/viral susceptibility). "Illumina review: Evidence suggests that susceptibility to infection-induced acute encephalopathy-4 (IIAE4) is conferred by heterozygous or homozygous variation in the CPT2 gene on chromosome 1p32. PMID:20934285: Shinohara et al. (2011) - found 352C variant at a significantly higher frequency in 29 Japanese patients with IIAE compared to controls. Pathogens included influenza, adenovirus, HHV6. mycoplasma and rotovirus. No correlation between good and poor prognosis. PMID: 21697855: Mak et al. (2011) - Showed heterozygosity for the CPT2 F352C variant and homozygosity for the CPT2 V368I variant in two unrelated Chinese individuals with fatal virally-induced acute encephalopathy. PMID: 15811315: Chen et al. (2005) - thermolabile phenotype of compound heterozygotes for F352C and V368I which showed a higher frequency in Japanese influenza-associated encephalopathy patients than healthy volunteers. PMID 18306170: Yao et al. (2008) - large proportion of patients suffering from disabling or fatal IAE, with transiently elevated serum acylcarnitine during high fever, exhibit a thermolabile phenotype of compound homozygous/heterozygous variants in CPT2. Among the variants, three compound variations found in patients with severe encephalopathy; [c.1055T>G (p.Phe352Cys); c.1102G>A (p.Val368Ile)], [c.1511C>T (p.Pro504Leu); c.1813G>C (p.Val605Leu)], and [c.1055T>G (p.Phe352Cys); c.1102G>A (p.Val368Ile); c.1813G>C (p.Val605Leu)], showed reduced activities, thermal instability, and short half-lives compared with the wild type. |
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| COVID-19 research v1.1 | DAG1 |
Rebecca Foulger changed review comment from: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): The DAG1 gene encodes 2 dystroglycan proteins, both of which are dystrophin-associated glycoproteins (DAGs) (OMIM:128239). Alpha-Dystroglycan (a-DG) is a common receptor for lymphocytic choriomeningitis virus (LCMV) and several other arenaviruses including the human pathogenic Lassa fever virus (Imperiali et al. 2005; Kunz et al. 2009; Rojek et al. 2007). PubMed 16254364: Imperiali et al. (2005) - alpha-Dystroglycan (a-DG) was identified as a common receptor for lymphocytic choriomeningitis virus (LCMV) and several other arenaviruses including the human pathogenic Lassa fever virus. Arenaviruses are enveloped, single-stranded RNA viruses with a bisegmented ambisense genome. Susceptibility toward LCMV infection differed in various cell lines despite them expressing comparable levels of DG, suggesting that posttranslational modifications of a-DG would be involved in viral receptor function. Demonstrated that glycosylation of a-DG, and in particular, O mannosylation, which is a rare type of O-linked glycosylation in mammals, is essential for LCMV receptor function. Cells that are defective in components of the O-mannosylation pathway showed strikingly reduced LCMV infectibility. As defective O mannosylation is associated with severe clinical symptoms in mammals such as congenital muscular dystrophies, it is likely that LCMV and potentially other arenaviruses may have selected this conserved and crucial posttranslational modification as the primary target structure for cell entry and infection. PMID 19324387: Kunz et al. (2009) - Old World arenaviruses LCMV (lymphocytic choriomeningitis virus) and LASV (Lassa virus) enter the host cell predominantly via a novel and unusual endocytotic pathway independent of clathrin, caveolin, dynamin, and actin. Infection of cells with LCMV and LASV depends on DG, this unusual endocytotic pathway could be related to normal cellular trafficking of the DG complex. Arenavirus particles may target DG for an endocytotic pathway not normally used in uninfected cells thereby inducing an entry route specifically tailored to the pathogen's needs. PMID 17360738: Rojek et al. (2007) - Found that protein O mannosylation of α-DG is crucial for the binding of arenaviruses of distinct phylogenetic origins, including LFV, Mobala virus, and clade C New World arenaviruses. Observed that overexpression of LARGE in cells deficient in O mannosylation resulted in highly glycosylated α-DG that was functional as a receptor for arenaviruses. Demonstrate that arenaviruses recognize the same highly conserved O-glycan structures on α-DG involved in ECM protein binding, indicating a strikingly similar mechanism of receptor recognition by pathogen- and host-derived ligands. PMID 21185048: Oldstone et al. (2011) - Dendritic cells (DC)s express the highest levels of α-DG and are the sentinel cells that LCMV, and presumably also LFV, infect. The resultant infection of DCs compromises DC function. Determinant of injury is the displacement of laminin or other ECM molecules that bind to the same site on α-DG that LCMV and LFV seek. When ECM molecules are pushed aside, the virus destabilizes membranes and causes interference with ECM signals that are required to maintain homeostasis. PMID 15857984: Kunz et al. (2005) Show that LFV (Lassa fever virus) binds to α-DG with high affinity in the low-nanomolar range. Recombinant vesicular stomatitis virus pseudotyped with LFV glycoprotein (GP) adopted the receptor binding characteristics of LFV and depended on α-DG for infection of cells. LFV was found to efficiently compete with laminin α1 and α2 chains for α-DG binding. LCMV uses the same domains of α-DG for binding that are used in LFV binding. Findings indicate a high degree of conservation in the receptor binding characteristics between the highly human-pathogenic LFV and murine-immunosuppressive LCMV isolates.; to: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): The DAG1 gene encodes 2 dystroglycan proteins, both of which are dystrophin-associated glycoproteins (DAGs) (OMIM:128239). Alpha-Dystroglycan (a-DG) is a common receptor for lymphocytic choriomeningitis virus (LCMV) and several other arenaviruses including the human pathogenic Lassa fever virus (Imperiali et al. 2005; Kunz et al. 2009; Rojek et al. 2007). PubMed 16254364: Imperiali et al. (2005) - alpha-Dystroglycan (a-DG) was identified as a common receptor for lymphocytic choriomeningitis virus (LCMV) and several other arenaviruses including the human pathogenic Lassa fever virus. Arenaviruses are enveloped, single-stranded RNA viruses with a bisegmented ambisense genome. Susceptibility toward LCMV infection differed in various cell lines despite them expressing comparable levels of DG, suggesting that posttranslational modifications of a-DG would be involved in viral receptor function. Demonstrated that glycosylation of a-DG, and in particular, O mannosylation, which is a rare type of O-linked glycosylation in mammals, is essential for LCMV receptor function. Cells that are defective in components of the O-mannosylation pathway showed strikingly reduced LCMV infectibility. As defective O mannosylation is associated with severe clinical symptoms in mammals such as congenital muscular dystrophies, it is likely that LCMV and potentially other arenaviruses may have selected this conserved and crucial posttranslational modification as the primary target structure for cell entry and infection. PMID 19324387: Kunz et al. (2009) - Old World arenaviruses LCMV (lymphocytic choriomeningitis virus) and LASV (Lassa virus) enter the host cell predominantly via a novel and unusual endocytotic pathway independent of clathrin, caveolin, dynamin, and actin. Infection of cells with LCMV and LASV depends on DG, this unusual endocytotic pathway could be related to normal cellular trafficking of the DG complex. Arenavirus particles may target DG for an endocytotic pathway not normally used in uninfected cells thereby inducing an entry route specifically tailored to the pathogen's needs. PMID 17360738: Rojek et al. (2007) - Found that protein O mannosylation of α-DG is crucial for the binding of arenaviruses of distinct phylogenetic origins, including LFV, Mobala virus, and clade C New World arenaviruses. Observed that overexpression of LARGE in cells deficient in O mannosylation resulted in highly glycosylated α-DG that was functional as a receptor for arenaviruses. Demonstrate that arenaviruses recognize the same highly conserved O-glycan structures on α-DG involved in ECM protein binding, indicating a strikingly similar mechanism of receptor recognition by pathogen- and host-derived ligands. PMID 21185048: Oldstone et al. (2011) - Dendritic cells (DC)s express the highest levels of α-DG and are the sentinel cells that LCMV, and presumably also LFV, infect. The resultant infection of DCs compromises DC function. Determinant of injury is the displacement of laminin or other ECM molecules that bind to the same site on α-DG that LCMV and LFV seek. When ECM molecules are pushed aside, the virus destabilizes membranes and causes interference with ECM signals that are required to maintain homeostasis. PMID 15857984: Kunz et al. (2005) show that LFV (Lassa fever virus) binds to α-DG with high affinity in the low-nanomolar range. Recombinant vesicular stomatitis virus pseudotyped with LFV glycoprotein (GP) adopted the receptor binding characteristics of LFV and depended on α-DG for infection of cells. LFV was found to efficiently compete with laminin α1 and α2 chains for α-DG binding. LCMV uses the same domains of α-DG for binding that are used in LFV binding. Findings indicate a high degree of conservation in the receptor binding characteristics between the highly human-pathogenic LFV and murine-immunosuppressive LCMV isolates. |
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| COVID-19 research v0.373 | IRF5 | Rebecca Foulger commented on gene: IRF5: PMID:29079574. Cevik et al., 2017 identify IRF5 as an important suppressor of HCV replication and HCC pathogenesis. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.364 | TLR5 |
Sarah Leigh changed review comment from: TLR5 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping). The transmembrane protein TLR5 is a component of the immune system that is highly expressed in intestinal mucosa and recognizes bacterial flagellin (PMID 20203013)(reviewed by Alison Coffey and team, Illumina). PMID 25395539 reports that mice treated with bacterial flagellin prevented rotavirus (RV) infection and cured chronically RV-infections. This processed required the flagellin receptors Tlr5 and Nlrc4. Flagellin-induced activation of Tlr5 on dendritic cells elicited production of the cytokine Il22, resulting in a protective gene expression program in intestinal epithelial cells. Administration of Il22 to mice reproduced the capacity of flagellin to prevent or cure RV. It was proposed that activation of innate immunity with flagellin, via Tlr5 inducing IL22 could be useful in preventing or curing viral infections.; to: TLR5 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping). The transmembrane protein TLR5 is a component of the immune system that is highly expressed in intestinal mucosa and recognizes bacterial flagellin (PMID 20203013)(reviewed by Alison Coffey and team, Illumina). PMID 25395539 reports that mice treated with bacterial flagellin prevented rotavirus (RV) infection and cured chronically RV-infections. This process required the flagellin receptors Tlr5 and Nlrc4. Flagellin-induced activation of Tlr5 on dendritic cells elicited production of the cytokine Il22, resulting in a protective gene expression program in intestinal epithelial cells. Administration of Il22 to mice reproduced the capacity of flagellin to prevent or cure RV. It was proposed that activation of innate immunity with flagellin, via Tlr5 inducing IL22 could be useful in preventing or curing viral infections. |
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| COVID-19 research v0.355 | TLR5 |
Sarah Leigh edited their review of gene: TLR5: Added comment: TLR5 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping). The transmembrane protein TLR5 is a component of the immune system that is highly expressed in intestinal mucosa and recognizes bacterial flagellin (PMID 20203013)(reviewed by Alison Coffey and team, Illumina). PMID 25395539 reports that mice treated with bacterial flagellin prevented rotavirus (RV) infection and cured chronically RV-infections. This processed required the flagellin receptors Tlr5 and Nlrc4. Flagellin-induced activation of Tlr5 on dendritic cells elicited production of the cytokine Il22, resulting in a protective gene expression program in intestinal epithelial cells. Administration of Il22 to mice reproduced the capacity of flagellin to prevent or cure RV. It was proposed that activation of innate immunity with flagellin, via Tlr5 inducing IL22 could be useful in preventing or curing viral infections.; Changed publications: 20203013, 25395539 |
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| COVID-19 research v0.349 | HDAC6 |
Rebecca Foulger commented on gene: HDAC6: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): Histone deacetylase 6 (HDAC6) is a unique cytoplasmic deacetylase that regulates various important biological processes by preventing protein aggregation and deacetylating different non-histone substrates. Growing evidence has indicated a dual role for HDAC6 in viral infection and pathogenesis: HDAC6 may represent a host defence mechanism against viral infection by modulating microtubule acetylation, triggering antiviral immune response and stimulating protective autophagy, or it may be hijacked by the virus to enhance proinflammatory response (Zheng et al, 2017). HDAC6 promotes the aggresome/autophagic degradation of the viral polyprotein Pr55Gag to inhibit HIV-1 production and infection (Hernández et al, 2019). Depletion of HDAC6 expression (in vitro) led to impaired antiviral responses against RNA viruses, but not against DNA viruses. HDAC6 knockout mice were highly susceptible to RNA virus infections compared to wildtype mice (Choi et al, 2016). Overexpression of Hdac6 enhances resistance to virus infection in embryonic stem cells and in mice (Wang et al, 2015). Literature: PMID: 27959772 - Zheng et al. (2017) (Review) This review highlights current data illustrating the complexity and importance of HDAC6 in viral pathogenesis. HDAC6 has both proviral and antiviral effects. HDAC6 can inhibit infection of both RNA and DNA virus by modulating microtubule (MT) cytoskeleton and stimulating selective autophagy and restrict viral diffusion by triggering antiviral immune response. However, RNA viruses can also utilize HDAC6-mediated aggresome pathway or proinflammatory response to facilitate viral pathogenesis (Fig 1 and Table 1) • HDAC6 triggers antiviral gene expression upon RNA virus infection (Fig 3a) • HDAC6 interacts with Vif or A3G and competes for Vif–A3G interaction through its BUZ domain, impairs the incorporation of Vif into nascent virions and finally controls HIV-1 infectiveness (Fig 4) • HDAC6 facilitates viral uncoating and pathogenesis (Fig 5) Findings support exploration of a potential therapeutic role for restricting viral pathogenesis by targeting HDAC6. PMID: 31736889: Hernández et al. (2019) - HIV Nef is a central auxiliary protein in HIV infection and pathogenesis. Results from the study indicate that HDAC6 promotes the aggresome/autophagic degradation of the viral polyprotein Pr55Gag to inhibit HIV-1 production • HIV-1 Nef viral protein induces HDAC6 Degradation (Enzyme degradation by recombinant HIV-1 Nef in HEK-293T cells in both endogenous and over expressed HDAC6 is shown in Fig 1) • Mutated Nef protein Nef-PPAA did not promote HDAC6 degradation (Figure 3A, quantified in Figure 3B). This fact may indicate that this motif is involved in Nef-mediated HDAC6 interaction and/or processing, or that a conformational change in the mutated viral protein abrogates the degradative activity observed with the wt-Nef (Figures 1–3) • Nef assures viral production and infection by targeting HDAC6, stabilizing Pr55Gag and Vif, thereby facilitating Pr55Gag location and aggregation at plasma membrane, and subsequent virus production and infection capacity (events summarized by schematic illustrations in Figure 10) PMID: 26746851: Choi et al. (2016) - HDAC6 plays an important role in the antiviral immune response by producing IFNs and proinflammatory cytokines in responses to foreign RNA viruses. HDAC6+/+ and HDAC6-/- mice were intravenously infected with vesicular stomatitis virus (VSV, Indiana strain). Results show that • HDAC6-/- mice are more susceptible to VSV-Indiana infection than HDAC6+/+ mice and showed significantly decreased survival rate (Fig 1A) • Virus titers were significantly higher and IFN-b and IL-6 production was markedly lower in HDAC6-/- mice than in HDAC6+/+ mice (Fig 1D and E) • Role of HDAC6 in cytokine induction by poly(I:C), which is a synthetic double-stranded RNA (dsRNA): Intravenous injection of poly(I:C) caused the rapid and robust induction of IFN-b and IL-6 in HDAC6+/+ mice; however, induction of these cytokines was significantly reduced in HDAC6-/-mice (Fig 1F). In vitro • HDAC6 deficiency reduces the innate immune response on mouse macrophage and mouse embryonic fibroblast (Fig 3) • HDAC6 and RIG-I transiently interact in response to RNA viral infection (Fig 5A and B) and HDAC6 regulates the binding of RIG-I to 50 pppdsRNA by deacetylating RIG-I (Fig 5G) PMID: 25482409 Wang et al. (2015) - This is another study that provides a proof of principle of antivirus function by Hdac6 in vivo. HDAC6 overexpression significantly enhances resistance to avian H5N1 virus infection and extends the survival rate in Hdac6tg mice (transgenic) (Fig 2). Also, ES cells overexpressing Hdac6 displayed resistance to infection by adenovirus at high titers (Fig 1). |
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| COVID-19 research v0.349 | DAG1 |
Rebecca Foulger commented on gene: DAG1: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): The DAG1 gene encodes 2 dystroglycan proteins, both of which are dystrophin-associated glycoproteins (DAGs) (OMIM:128239). Alpha-Dystroglycan (a-DG) is a common receptor for lymphocytic choriomeningitis virus (LCMV) and several other arenaviruses including the human pathogenic Lassa fever virus (Imperiali et al. 2005; Kunz et al. 2009; Rojek et al. 2007). PubMed 16254364: Imperiali et al. (2005) - alpha-Dystroglycan (a-DG) was identified as a common receptor for lymphocytic choriomeningitis virus (LCMV) and several other arenaviruses including the human pathogenic Lassa fever virus. Arenaviruses are enveloped, single-stranded RNA viruses with a bisegmented ambisense genome. Susceptibility toward LCMV infection differed in various cell lines despite them expressing comparable levels of DG, suggesting that posttranslational modifications of a-DG would be involved in viral receptor function. Demonstrated that glycosylation of a-DG, and in particular, O mannosylation, which is a rare type of O-linked glycosylation in mammals, is essential for LCMV receptor function. Cells that are defective in components of the O-mannosylation pathway showed strikingly reduced LCMV infectibility. As defective O mannosylation is associated with severe clinical symptoms in mammals such as congenital muscular dystrophies, it is likely that LCMV and potentially other arenaviruses may have selected this conserved and crucial posttranslational modification as the primary target structure for cell entry and infection. PMID 19324387: Kunz et al. (2009) - Old World arenaviruses LCMV (lymphocytic choriomeningitis virus) and LASV (Lassa virus) enter the host cell predominantly via a novel and unusual endocytotic pathway independent of clathrin, caveolin, dynamin, and actin. Infection of cells with LCMV and LASV depends on DG, this unusual endocytotic pathway could be related to normal cellular trafficking of the DG complex. Arenavirus particles may target DG for an endocytotic pathway not normally used in uninfected cells thereby inducing an entry route specifically tailored to the pathogen's needs. PMID 17360738: Rojek et al. (2007) - Found that protein O mannosylation of α-DG is crucial for the binding of arenaviruses of distinct phylogenetic origins, including LFV, Mobala virus, and clade C New World arenaviruses. Observed that overexpression of LARGE in cells deficient in O mannosylation resulted in highly glycosylated α-DG that was functional as a receptor for arenaviruses. Demonstrate that arenaviruses recognize the same highly conserved O-glycan structures on α-DG involved in ECM protein binding, indicating a strikingly similar mechanism of receptor recognition by pathogen- and host-derived ligands. PMID 21185048: Oldstone et al. (2011) - Dendritic cells (DC)s express the highest levels of α-DG and are the sentinel cells that LCMV, and presumably also LFV, infect. The resultant infection of DCs compromises DC function. Determinant of injury is the displacement of laminin or other ECM molecules that bind to the same site on α-DG that LCMV and LFV seek. When ECM molecules are pushed aside, the virus destabilizes membranes and causes interference with ECM signals that are required to maintain homeostasis. PMID 15857984: Kunz et al. (2005) Show that LFV (Lassa fever virus) binds to α-DG with high affinity in the low-nanomolar range. Recombinant vesicular stomatitis virus pseudotyped with LFV glycoprotein (GP) adopted the receptor binding characteristics of LFV and depended on α-DG for infection of cells. LFV was found to efficiently compete with laminin α1 and α2 chains for α-DG binding. LCMV uses the same domains of α-DG for binding that are used in LFV binding. Findings indicate a high degree of conservation in the receptor binding characteristics between the highly human-pathogenic LFV and murine-immunosuppressive LCMV isolates. |
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| COVID-19 research v0.349 | CXCL8 |
Rebecca Foulger commented on gene: CXCL8: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): • CXCL8 is a proinflammatory chemokine that plays a role in inflammatory response and immune cell trafficking • Multiple studies show IL-8 levels were shown to be elevated in plasma of patients with COVID-19, SARS-CoV, or MERS-CoV compared to controls. These include a number of recent COVID-19 studies (Coperchini et al. 2020). • Higher levels were detected in more severe cases (Gong et al. 2020; Qin et al. 2020; Yan et al. 2020), although one study shows the levels are within the normal range (Qin et al. 2020) • Gong et al. (2020) suggest that IL-8 might be a therapeutic target COVID-19 Literature: PMID 32446778; Coperchini et al. (2020) • Review article describing the involvement of chemokine/chemokine-receptor system in COVID-19 • Discusses the concept of cytokine storm where the immune system is ‘attacking’ the body resulting in acute respiratory distress syndrome. • Multiple studies are mentioned that show high levels of CXCL8 in the plasma and broncho-alveolar fluid in patients with acute respiratory distress syndrome. Reference a paper that notes that pre-treatment with an anti-CXCL8 antibody prevented acute lung injury that generally develops. • In vivo studies showed elevated CXCL8 in patients with SARS-CoV. • In vitro studies where peripheral blood mononuclear cells from healthy donor inoculated with SARS-CoV showed enhancement in the expression of CXCL8 • Similarly, CXCL8 was upregulated in cells lysates when with MERS-CoV infection of polarized airway epithelial cells (higher expression than SARS-CoV). • Higher plasma levels of CXCL8 in patients with COVID-19 compared to healthy controls; however, transcription of CSCL8 was not upregulated MedRxiv; Gong et al. (2020) • Evaluated disease severity in a total of 100 patients with COVID-19 pneumonia • CXCL8 (IL-8 in this paper) was detected in these patients and IL-8 levels were shown to be associated with disease severity (P<0.001); significant differences were noted between critical and severe patients or critical and mild groups (Tables 2 and 3) • Suggest that IL-8 might be a therapeutic target COVID-19 PMID 32161940; Qin et al. (2020) • Retrospective study of 452 patients with COVID-19; severity of COVID-19 defined according to the Fifth Revised Trial Version of the Novel Coronavirus Pneumonia Diagnosis and Treatment Guidance • Clinical and laboratory data were collected • A majority of the severe cases (n=286) had elevated levels of IL-8 (18.4 pg/mL vs 13.7 pg/mL, respectively; p<0.001) compared to the nonsevere cases (n=166), although they were all in the normal (0-62.0 pg/mL) (Table 2) MedRxiv; Yan et al. (2020) • Identified 25 genes that showed highly conserved kinetics in COVID-19 patients • Figure 3F shows expression of CXCL8 and plasma levels of IL-8 from four individuals with COVID-19 compared to four healthy controls was higher in patients especially in the severe stage (p<0.001) PMID 15585888; Chang et al. (2004) • Introduction has a summary of previously published papers and notes that high serum levels of IL-8 were detected during acute phase and associated with lung lesions in patients with SARS in one study. Another study suggests use of corticosteroids in reducing pulmonary inflammation due to IL-8. • Chang et al. (2004) used transient transfection of the SARS-CoV S protein-encoding plasmid on the IL-8 promoter. Measure of IL-8 release in lung cells showed an upregulation of IL-8 release. In addition, a specific region of the S protein was identified as a potentially important region for inducing IL-8 release. There are additional case-control studies suggesting possible association of polymorphisms in CXCL8 and acute bronchiolitis susceptibility (Pinto et al. 2017; PMID 27890033), asthma (Charrad et al. 2017; PMID 28993876), or human papillomavirus infection (weaker evidence; Junior et al. 2016; PMID 27783717). |
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| COVID-19 research v0.349 | RNASEL |
Rebecca Foulger commented on gene: RNASEL: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): RNASEL, also known as 2-5A-dependent RNase is a component of the interferon-regulated 2-5A system that functions in the antiviral interferon pathway. Treatment of cells with interferon results in enhanced levels of both 2-5A-dependent RNase and a group of synthetases that produce 5-prime-triphosphorylated, 2-prime,5-prime-oligoadenylates (2-5A) from ATP. The role of the 2-5A system in the control of viral and cellular growth suggests that defects in the 2-5A-dependent RNase gene could result in reduced immunity to virus infections and cancer (Hassel et al., 1993). Several studies aiming to identify a genetic association between RNASEL and viral susceptibility have failed to identified statistically significant SNPs (Yakub et al. 2005; Arredondo et al. 2012). However, there is sufficient experimental evidence, including a mouse model and in-vitro studies that RNASEL is an important contributor in host defence against several viruses (Gusho et al. 2016 (review); Zhou et al. 1997; Panda et al. 2019). PMID 27595182: Gusho et al. 2016 (review) - RNase L is a unique IFN-regulated endoribonuclease that serves as an important mediator of antiviral innate immunity with possible roles in antibacterial defense and prostate cancer. It is controlled by IFN-inducible oligo-adenylate synthetases (OASs) and double-stranded RNAs (dsRNAs). OAS-RNase L (Fig. 1) pathway, discovered in the mid-1970s, was one of the first IFN-dependent antiviral pathways to be characterized. OASs are IFN-I/-III-inducible genes that are expressed at very low basal levels in many cell types. OASs1-3 act as pathogen recognition receptors that sense dsRNAs and activate the synthesis of 5’-phosphorylated 2’-5’ linked oligoadenylates from ATP (2-5A). 2-5A acts as a second messenger and binds monomeric RNase L, and activates its dimer formation. Active RNase L cleaves cellular and viral RNAs within single-stranded regions. RNA degradation directly and indirectly activates subsequent events, including the elimination of viral genomes, inhibition of cellular and viral protein synthesis; and activation of several cellular signaling pathways, including those involved in autophagy, apoptosis, senescence, IFN-b production, and NLRP3-inflammasome activation as part of its antiviral mechanism (references provided). Authors state that many viruses have evolved or acquired strategies that antagonize the OAS-RNase L pathway to evade antiviral innate immunity. Some, such as Influenza A (IAV), HSV and Vaccinia virus act through an RNA-binding domain which binds to and sequesters dsRNA, the activator of OAS. Others bind directly to monomeric RNase L preventing it from activation by dimerization. Some coronaviruses (MERS-CoV and MHV) are described to act through their ns-domains with 2’-5’ PDE activity that degrades 2-5A and thus prevent activation of RNase L. Some additional evidence of interest: -OAS3 was shown to exert antiviral activity against Dengue virus in an RNase L-dependent manner, indicating that OAS3 synthesizes active 2-5A in sufficient amounts for RNase L activation -RNase L activation by dsRNA signaling or viral infection contributes to IFN-b production, indicating its important role in innate immunity. The ribonuclease function of RNase L is essential for its effect on IFN-b production -Moreover, mice deficient in RNase L had several-fold reduced levels of IFN-b induction after infection with RNA viruses (EMCV and Sendai virus) -Stable expression of wild-type human full-length RNase L, but not ribonuclease dead mutant (R667A), activates IL-1b and caspase 1 secretion in RNase L-deficient THP1 cells after virus infection or 2-5A transfection PMID 9351818: Zhou et al. (1997) RNASEL Mouse model To determine the physiological roles of the 2-5A system, mice were generated with a targeted disruption of the RNase L gene. The antiviral effect of interferon was impaired in RNaseL–/– mice providing the first evidence that the 2-5A system functions as an antiviral pathway in animals. Authors showed that EMCV replicates more efficiently in cells lacking RNase L than in wild type cells, even after interferon treatment, although the effect is relatively small. Next, authors determined that survival of RNaseL-/- mice after EMCV infection was significantly reduced both in presence and absence of IF (Fig 3). Enlarged thymus and reduced level of apoptosis in thymus and spleen were also found (Fig 4-5). PMID 31156620 Panda et al (2019) Interferon regulatory factor-1 (IRF1) regulates expression of RNaseL and knockdown of RNaseL in BEAS-2B cells resulted in significantly increased VSV infection rates. (Fig.6) PMID 22356654 Arredondo et al. 2012 Authors studied allelic variants in RNASEL gene at codon 462 (R462Q, rs486907) for susceptibility to viral infection, prostate cancer and chronic fatigue syndrome. The allelic distribution at codon 462 was 139 (33.9%), 204 (49.8%), and 67 (16.3%) for RR, RQ, and QQ, respectively, in 410 individuals in Spain. There were no significant differences comparing 105 blood donors and 71 patients with HIV-1 infection, 27 with chronic hepatitis C, 67 with prostate cancer, and 107 with chronic fatigue syndrome. In contrast, two-thirds of 18 patients with HTLV-1 infection and 15 with chronic hepatitis B harbored RR (Table 1). Thus, polymorphisms at the RNASEL gene do not seem to influence the susceptibility to common viral infections or conditions potentially of viral etiology. They conclude that the role in influencing the susceptibility to HTLV-1 or HBV chronic infection warrants further examination in larger patient populations. |
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| COVID-19 research v0.349 | PVR |
Rebecca Foulger commented on gene: PVR: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): PVR, or CD155, belongs to a large family of immunoglobulin (Ig)-like molecules called nectins and nectin-like proteins, which mediate cell-cell adhesion, cell migration, and cell polarization through interaction with other nectins. It is both a viral receptor and immunomodulatory protein and is involved in many biological processes. PVR serves as the entry receptor for poliovirus and thereby is responsible for human susceptibility to poliovirus infection. Susceptibility to poliovirus is a function of the presence or absence of the cellular receptor to which the virus binds as the first step in poliovirus replication. Mendelsohn et al. (1986) succeeded in transforming a human poliovirus receptor gene into mouse L cells, which are ordinarily resistant to poliovirus infection because they do not bear a poliovirus receptor. Monoclonal antibody directed against the HeLa cell poliovirus receptor site was used in rosette assays to identify poliovirus-sensitive transformants. Evidence for PVR as a Viral Receptor, regulator of immune function and its role in cancer is described in Bowers et al (2017). CD155-deficient mice develop normally without displaying an overt phenotype. However, the animals are distinguished by distinct deficits in the development of a regular humoral immune response (Maier et al, 2007) Literature: PMID: 28870470 - Bowers et al, 2017 (Review) - PVR is an important cell adhesion protein and is involved in the transendothelial migration of leukocytes. PVR undergoes alternative splicing, generating 4 unique splice forms. Protein isoforms and interactions with Poliovirus are summarized in Table 1. In addition to its role as a receptor for the human poliovirus, several native biological functions have also been uncovered. PVR is an important cell adhesion protein and is involved in the transendothelial migration of leukocytes. Through its interactions with CD226 and TIGIT, transmembrane proteins found on leukocytes, PVR is a key regulator of the cell-mediated immune response. In this review more evidence is available for PVR as a Viral Receptor and PVR as a regulator of immune function PMID: 25113908 - Bolduan et al, 2014 - NL4-3 Vpu protein from HIV downregulates the activating NK cell receptor CD155 from the cell surface by the conserved alanine residues Ala-10, Ala-14 and Ala-18 of its TM domain to evade NK cell mediated immune response against HIV-1 infected cells (Hela cells) PMID: 19815499 - Stanietsky et al, 2009 - TIGIT (a protein expressed by all human NK cells) binds PVR and PVRL2 but not PVRL3 and inhibits NK cytotoxicity directly through its ITIM. PMID: 12943679 - Baury et al, 2003 -As the extracellular domains of the sPVR (soluble PVR) isoforms are identical to the extracellular domain of transmembrane PVR, they can compete with transmembrane PVR for the canyon-like receptor binding site of poliovirus. When sPVR is overexpressed in poliovirus susceptible HeLa cells, it significantly reduces viral entry and viral infectivity PMID: 17621371 - Maier et al, 2007 - In this study, Maier et al explore the expression profile of CD155 on murine hematopoietic cells utilizing newly generated mAb. They report on the establishment and immunological analysis of mice deficient in CD155. CD155-deficient mice (knock out) develop normally without displaying an overt phenotype. However, the animals are distinguished by distinct deficits in the development of a regular humoral immune response. Whereas systemic challenges revealed no differences, orally administered antigen evoked less efficient IgG and IgA antibody responses (Figure 7) despite of normal IgM titers when compared to wild-type mice. Therefore, CD155 may assist in an efficient humoral immune response generated within the intestinal immune system. PMID: 28800489 - Lin et al, 2017 - Amino acid changes in the C’C”D region in poliovirus receptor domain 1 disrupt poliovirus binding. We substituted this region of Pvr into the corresponding region of a murine homolog, nectin-2. The chimeric receptor, nectin-2Pvr(c'c"d), rendered transformed L cells susceptible to infection with poliovirus P1/Mahoney, but not with polioviruses P2/ Lansing and P3/Leon, due to lack of binding. PMID: 2597248 - Kanemaru et al, 2015 - Mice genetically deficient in CD155 or treated with anti-CD155 Ab exhibited attenuated Th1-type contact hypersensitivity. Thus, CD155 plays an important regulatory role in helper T cell differentiation and allergic diseases. |
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| COVID-19 research v0.348 | PTX3 |
Rebecca Foulger commented on gene: PTX3: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): Pentraxins are a superfamily of conserved humoral mediators of innate immunity. PTX3, the prototypic long pentraxin, is a soluble pattern recognition molecule produced by several cell types in response to primary pro-inflammatory signals and microbial recognition. It is involved in the initiation of protective responses against select pathogens, acting as an important mediator of innate immunity against pathogens of fungal, bacterial and viral origin, and as a regulator of inflammation, by modulating complement activation and cell extravasation, and facilitating pathogen recognition by myeloid cells. It is an established biomarker in sepsis, with PTX3 plasma levels associated with severity of the condition, patient survival, and response to therapy. PTX3 has been characterized as a biomarker of severity and outcomes in different infections caused by bacteria, fungi or viruses. Patients with pulmonary aspergillosis, tuberculosis, dengue virus infection, meningococcal disease leptospirosis and shigellosis have increased PTX3 plasma levels that correlate with disease severity and could act as predictor of unfavourable outcomes (PMID 31031772: Porte et al. 2019). Several studies using Ptx3-deficient mice showed an increased susceptibility to fungal, bacterial and viral pathogens (Porte et al. 2019). In contrast, a study in PTX3-deficient (PTX3(-/-)) mice acutely infected with RRV exhibited delayed disease progression and rapid recovery through diminished inflammatory responses and viral replication (Foo et al. 2015). PTX3 administration has shown to be protective also against infections with Influenza virus, murine cytomegalovirus, Neisseria meningitidis, and P. aeruginosa in neonates and during chronic infections by reducing viral load and inflammatory pathology. (PMID 31031772: Porte et al. 2019, PMD 18292565: Reading et al. 2008). PMID: 25695775: Foo et al. (2015) - Found that pentraxin 3 (PTX3) was highly expressed in chikungunya virus (CHIKV) and Ross River virus (RRV) patients during acute disease. Overt expression of PTX3 in CHIKV patients was associated with increased viral load and disease severity. PTX3-deficient (PTX3(-/-)) mice acutely infected with RRV exhibited delayed disease progression and rapid recovery through diminished inflammatory responses and viral replication. Furthermore, binding of the N-terminal domain of PTX3 to RRV facilitated viral entry and replication. PMID: 18292565 - Reading et al. (2008) - Identified the long pentraxin PTX3 as a potent innate inhibitor of influenza viruses both in vitro and in vivo. Human and murine PTX3 bound to influenza virus and mediated a range of antiviral activities, including inhibition of hemagglutination, neutralization of virus infectivity and inhibition of viral neuraminidase. Antiviral activity was associated with binding of the viral hemagglutinin glycoprotein to sialylated ligands present on PTX3. Using a mouse model found PTX3 to be rapidly induced following influenza infection and that PTX3-/- mice were more susceptible than wild-type mice to infection by PTX3-sensitive virus strains. Therapeutic treatment of mice with human PTX3 promoted survival and reduced viral load in the lungs following infection with PTX3-sensitive, but not PTX3-resistant, influenza viruses. PMID 19968561: Bottazzi et al. (2010) (Review) - PTX3 binds to human and murine cytomegalovirus and influenza virus type A (IVA). The interaction between PTX3 and IVA occurs through binding of sialylated ligands on PTX3 to the viral hemagglutinin and results in neutralization of virus infectivity in vitro. Consistently, desialylated PTX3 does not bind IVA and does not neutralize virus infectivity. |
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| COVID-19 research v0.348 | NPC1 |
Rebecca Foulger commented on gene: NPC1: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): NPC1 encodes a polytopic protein that resides in the limiting membrane of late endosomes and lysosomes (LE/LY) and mediates distribution of lipoprotein-derived cholesterol in cells (Cote et al. (2011). NPC1 expression is critical for filovirus infection (EboV and MarV) and the mechanism of infection is not dependent on NPC1 cholesterol transport activity (Carette et al. 2011). Structural studies demonstrate that the C-domain of NPC1 binds to the primed EBOV glycoprotein (Wang et al. 2016; Gong et al. 2016). PMID 21866103: Carette et al. (2011) Genome-wide haploid genetic screen was performed in primary fibroblasts derived from human Niemann-Pick type C1 disease patients to identify host factors required for Filovirus infection. These cells are resistant to infection by EboV and MarV but remain fully susceptible to other unrelated viruses (Figure 2A, B). Resistance of NPC1-deficient cells was not caused by cholesterol transport defects (Fig S8). Infection in these cells was restored by expression of wild type NPC1 (Figure 2C). Similar results were observed in NPC1-null Chinese hamster ovary (CHO) cells, with loss of NPC1 conferring complete resistance to viral infection (Figure S6D) that was reversed by expression of human NPC1 (Figure S6E). Electron micrographs of NPC1 mutant cells infected with rVSV-GP-EboV indicate that NPC1 is required in downstream process in filovirus entry leading to viral membrane fusion and escape from the lysosomal compartment. Knockdown of NPC1 in HUVEC diminished infection by filoviruses (Figure 4D and S18) suggesting that NPC1 is critical for authentic filovirus infection. Furthermore, NPC1+/+ mice rapidly succumb to infection with either filovirus while NPC1−/+ mice were largely protected (Figure 4E). PMID 2186610: Cote et al. (2011) HeLa cells treated with benzylpiperazine adamantane diamide-derived compounds (3.0 and 3.47) developed cytoplasmic vacuoles indicating that that they target one or more proteins involved in regulation of cholesterol uptake in cells. CHO cells lacking NPC1 were completely resistant to infection by this virus and infection of these cells was fully restored when NPC1 was expressed. NPC1 expression but not NPC1-dependent cholesterol transport activity is essential for EboV infection (Fig 2c). 3.0-derived compounds inhibit EboV infection by interfering with binding of cleaved glycoprotein to NPC1 (Fig 4). PMID 26771495: Wang et al. (2016) The crystal structure of the primed glycoprotein (GPcl) of Ebola virus and domain C of NPC1 (NPC1-C) demonstrates that the NPC1-C binds to the primed EBOV GP (Fig 1, 3). Further, it suggests that a membrane-fusion-priming conformational change occurs in GPcl or the binding of GPcl, and this is a unique feature for all the filoviruses. NPC1-interacting compound 3.47 competitively blocks the primed GP binding to the membrane probably binds to the two protruding loops of NPC1-C. Compound U18666A binds to a different site on NPC1 causing endosomal calcium depletion. Furthermore, peptide inhibitors or small molecules, which can easily penetrate the cell membrane and reach the primed GP in the late endosomes could also act as potential therapeutic agents. PMID 27238017: Gong et al. (2016) Full-length human NPC1 and a low-resolution reconstruction of NPC1 in complex with the cleaved glycoprotein (GPcl) of EBOV was determined by single-particle electron cryomicroscopy. NPC1 contains 13 transmembrane segments (TMs) and three lumenal domains, A (NTD), C, and I. TMs 2–13 exhibit a typical resistance-nodulation-cell division fold, among which TMs 3–7 constitute the sterol-sensing domain conserved in several proteins involved in cholesterol metabolism and signaling. EBOV-GPcl binds to NPC1 through the domain C. |
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| COVID-19 research v0.348 | NECTIN1 |
Rebecca Foulger commented on gene: NECTIN1: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): Amino acid substitutions in nectin-1 showed impaired entry of Herpes simplex virus (HSV) into CHO-K1 cells (PMID:1175687;12072525). Nectin-1 knockout mice inoculated with HSV in the hippocampus demonstrated that nectin-1 is necessary for neurologic disease caused by HSV (PMID:19805039). PMID 11756979 - Struyf et al. (2002) - Searched for polymorphisms in HVEM, nectin-1, and nectin-2 via sequencing in individuals shown to immune seronegative for herpes simplex virus (HSV). These individuals showed T cell responses to HSV antigens and did not have anti-HSV antibodies detected in their serum. There were three individuals that were immune seronegative, three with no signs of cellular or humoral immunity, and three with frequent reactivations of HSV who had antibody and T cell responses to HSV. One individual in the study (true seronegative as demonstrated by negative testing for HSV-1 and HSV-2 and no HSV-specific T cell immunity) was identified to have a variant in nectin-1 (c.752G>A, p.Arg199Gln) in addition to one missense variant in HVEM (table 2). This variant was screened for 644 healthy White individuals and 17 were shown to be heterozygous for the p.Arg199Gln variant and one individual had a different missense variant at the same residue. The p.Arg199Gln variant occurs in the first constant-like domain for the protein. A different domain, the N-terminal variable-like domain, has previously been shown as important for virus entry into the cell. PMID 12072525 - Martinez and Spear (2002) - Investigated whether residues 75-77 and 85 of nectin-1 (homologous to regions A and B of nectin-2) are necessary for HSV-1 entry into CHO-K1 cells (which are resistant to the entry of alphaherpesviruses unless they are created to express a gD receptor). When there were mutants involving both residues 77 and 85, there was severely diminished ability of HSV-1 or HSV-2 to enter the cell and was unable to find to soluble forms of HSV-1 and HSV-2 (table 1; fig. 3). Note that these mutants allowed entry of PRV and BHV-1. PMID 19805039 - Kopp et al. (2009) - Nectin-1 knockout (KO) mice were inoculated intracranially and into the hippocampus with herpes simplex virus (HSV) and infection of neurons compared to HVEM KO mice, HVEM/nectin-1 KO mice, and controls. Nectin-1 KO mice were resistant to disease, as were the double KO mice at doses of the virus up to 100x needed to cause disease as compared to the wildtype and HVEM KO mice (Fig. 1). Nectin-1 is necessary for neurologic disease caused by HSV. Viral antigen was not detected in brain sections from double KO mice, but could be detected for nectin-1 KO mice (limited regions), HVEM-KO mice and wildtype (more widespread) (Fig. 2A). HSV was shown to be located to the ventricular surfaces in nectin-1 KO mice and confirmed as non-parenchymal cells (Fig. 2B). |
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| COVID-19 research v0.348 | IRF2 |
Rebecca Foulger commented on gene: IRF2: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): IRF2 encodes interferon regulatory factor 2, a member of the family of transcription factors that play a role in regulating both the innate and adaptive immune response. IRF2 is an antiviral IFN-stimulated gene (ISG) which negatively regulates IFN signalling. (Lukele et al. 2019 -review). In both cell culture and the knock out Irf2-/- mouse model, Irf2 deficiency leads to an increase in susceptibility to viral infection (Schoggins et al. 2011; Karki et al. 2012; Matsuyama et al. 1993; Grieder et al. 1999). Irf2-/- mice also show increased susceptibility to neurotrophic viruses, including SINV and VSV, when compared to wild type mice. The compromised development and maturation of multiple immune cell types in the Irf2−/− mice which lead to reduced B cells and virus specific IgG levels in the brains of infected mice was linked to the pathogenic phenotype (Melody et al. 2016). These data suggest IRF2 may also play an important role in the development of the immune system. PMID: 21478870 Schoggins et al. (2011) - The authors over expressed over 380 ISGs to test their ability to inhibit the replication of viruses including hepatitis C virus (HCV), yellow fever virus (YFV), West Nile virus (WNV), chikungunya virus (CHIKV), Venezuelan equine encephalitis virus (VEEV), and human immunodeficiency virus (HIV-1). Each gene was expressed in a lentiviral construct transfected into various cell lines. Cells were challenged with GFP expressing virus and replication was quantified by flow cytometry. IRF2 was shown to be a anti-HCV ISGs. PMID: 22615998 Karki et al. (2012) - Karki et al. used a library of lentiviruses individually expressing more than 350 ISGs, transduced in HuH-7 cells in the presence of absence of ZAP and identified IRF2 as an enhancer of viral inhibition upon infection with SINV. In confirmatory experiments, when both ZAP and IRF2 were knocked down, viral replication was significantly increased compared to ZAP or IRF2 silencing alone, which supports the results obtained in the ISG overexpression screen and suggests that endogenous ZAP and IRF2 might interact in a synergistic manner (Fig. 5). PMID: 10208925 Grieder et al. (1999) - Irf2−/− mice show increased susceptibility to virulent Venezuelan equine encephalitis (VEE) virus infection even after vaccination with attenuated VEE, suggesting IRF2 is required to mount a protective immune response (Grieder and Vogel, 1999) PMID: 22113474 Gao et al. (2012) - The authors found IRF2 variants to be risk alleles for atopic dermatitis and eczema herpeticum. Eight SNPs were found to be significantly associated with reduced IFN-γ production after stimulation with herpes simplex virus. In the cohort, none of the SNPs showed association with HSV positivity. PMID: 27899441 Melody et al. (2016) - Fig 1. Lrf2 mice show lethality upon peritoneal infection with either SINV or VSV virus (Fig 1) Irf2−/− and WT mice were challenged i.p. with SVN, a neurovirulent but noninvasive strain, which normally replicates only in the periphery without lethality in mice. Approximately 70% of the Irf2−/− mice succumbed to infection with SVN, whereas all of the WT littermate control mice survived (Fig. 1 A), indicating that IRF2 deficiency confers lethal neuroinvasive properties on the normally noninvasive SVN strain. Infection with VSV led to survival of all the WT mice, whereas ∼60% of the Irf2−/− mice suffered from paralysis and succumbed to infection. Staining using Evans blue showed that the integrity of the blood brain barrier is maintained during the infection(fig 2). The survival of lrf-/- mice treated with IFNAR-1 blocking antibody at 2dpi was similar to treatment with a control antibody, suggesting that peripheral elevation of type I IFN signalling is not responsible for the susceptibility (fig 3). Development and maturation of multiple immune cell subsets are compromised in Irf2−/− mice at baseline and upon SVN infection. B cells and virus-specific IgG level are significantly reduced in Irf2 -/- mouse brains, periorbital injection of naïve Bcells from WT mice 1day before infection did not affect lethality in the lrf2-/1 mice. |
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| COVID-19 research v0.348 | DICER1 |
Rebecca Foulger changed review comment from: Evidence Summary from Illumina curation team: The DICER1 gene, located on chromosome 14, position q32.13, was discovered in 2001 by Bernstein and is a member of the RNase III family, (also known as dicer 1, ribonuclease III; dicer1, Dcr-1 homolog (Drosophila); multinodular goitre 1). DICER1 is involved in the generation of double-stranded microRNAs (miRNAs), short non-coding RNAs, the cleavage of dsRNA into siRNAs, along with the biogenesis of numerous other small RNAs. There is increasing evidence DICER1 is also involved in regulating many other essential cellular processes such as those related to chromatin remodeling, inflammation, apoptosis and cell survival (Kurzynska-Kokorniak et al. 2015; Song and Rossi, 2017). DICER1 encodes a ∼220-KDa protein (RNase III endoribonuclease) which is a crucial component of the RNA Induced Silencing Complex (RISC) loading complex (RLC), comprised of dicer, Argonaute-2 (AGO-2), and trans-activation-responsive RNA binding protein 2 (TARBP2). The encoded protein is required by the RNA interference (RNAi) and small temporal RNA (stRNA) pathways to produce the active small RNA component which has a role in modulating gene expression at the post-transcriptional level. Research has shown that expression levels of cellular transcript and protein dicer are strictly controlled, with aberrant regulation contributing to carcinogenesis, neurodegenerative, rheumatic and immune system disorders. Studies have concluded that the encoded dicer ribonuclease-dependent processing of dsRNA viral replication intermediates into successive siRNAs is a conserved mammalian immune response to infection by positive-strand RNA viruses (Svobodova et al. 2016 summary & fig1; Li et al. 2013; Ding et al. 2018). Moreover, miRNAs play an important role in host-virus interactions in mammals (See Maillard et al. 2019 REVIEW; Foulkes et al. 2014 REVIEW). IMMUNE SYSTEM The cre-lox method for dicer1 gene knockout has been employed for studies into the role of dicer1 in immune cell development and function. Studies of dicer1 fl/fl mice have indicated short survival times along with severely impaired GMP differentiation into monocytes, neutrophils, myeloid DCs & mature macrophages. (Devasthanam et al. 2014). Results conclude that dicer1 is important in immune response and also vital for cell survival and apoptosis pathways. Muljo et al. (2005) investigated a conditional allele of dicer-1 (dcr-1) within a mouse model and showed that specific dcr-1 deletion in the T-cell lineage, resulted in impaired development of T-cells & aberrant cell differentiation of T-helper cells & cytokine production. Dcr-1 deletion in the thymus resulted in severe block in development of CD8+ T cells and resulted in defective microRNA processing in CD4+ T-cells. The results demonstrate Dicer regulates diverse aspects of T-cell biology along with cytokine production during T-cell differentiation where dicer-deficient T-cells preferentially express interferon-ƴ. VIRUSES Research by Galiana-Arnoux et al. (2006), of DICER in drosophila (drosophila have two dicer genes) have identified that DICER genes (Dcr1, miRNA pathway and Dcr2, RNAi pathway) control production of siRNA and a loss-of-function mutation in Dcr2 resulted in increased susceptibility to three different families of RNA viruses. Qi et al. (2012) research into RNAi gene silencing mechanism show that the B2 protein in Wuhan nodavirus (WhNV) suppresses Dcr2 in drosophila by direct interaction with the PAZ and RNAse III domains therefore blocking processing of dsRNA and siRNA. Evidence of a dicer antiviral system was also reported by Machitani et al. (2016) for mammalian human adenoviruses where DICER1 gene knockdown increased the copy number of adenovirus-encoding small RNAs (VA-RNAs) leading to the promotion of adenovirus replication; conversely, dicer overexpression significantly inhibited viral replication. Modai et al. (2019) conclude that HIV-1 infection inhibits DICER1 by altering miRNA expression. They conclude that upon HIV-1 infection, human miR-186, 210 and 222 directly regulate DICER1 gene expression causing down-regulation of the gene contributing to impaired cell-mediated immunity (fig6). Other methods of inhibition are from viral proteins, termed viral suppressors of RNA silencing, which interact and inhibit dicer ribonuclease activity in HIV-1 and hepatitis C infections. These viral proteins may mediate proteasomal degradation of endoribonuclease dicer through CRL4DCAF1 ubiquitin ligase complex (Klockow et al. 2013), interact directly via the core protein (Chen et al. 2008) or HIV-1 transactivation of transcription (Bennasser and Jeang, 2006). Through these methods they can block dicer interactions with TRBP2 or ADAR1, boost macrophage infection, and subsequently reduce the function of short hairpin RNAs (shRNAs) which thus inhibit RNA silencing. Ultimately these viruses, though various methods, supress the ability of dicer to process dsRNAs into siRNAs boosting viral infection and pathogenesis. Downregulation of DICER1 gene expression has additionally been found in cord blood of infants with severe respiratory syncytial virus (RSV), prior to RSV exposure, indicating this reduced expression may predispose newborns to RSV disease. Inchley et al. (2011) theorize that this occurs via disruption of leukocyte gene regulation of miRNA and direct anti-viral RNAi mechanisms. (Inchley et al. 2011 see section on “Dicer Gene Expression”). Otsuka et al. (2007) have shown using gene-trap methods to obtain viable dicer1 fl/fl mice where dicer1 deficiency caused impairment of miR24 and miR93 production resulting in susceptibility to vesticular stomatitis virus (VSV) and herpes simplex-1 virus, but not other viruses tested. SARS CoV & SARS CoV-2 Recently, Pasquier and Robichon, 2020 (preprint) have investigated the Dicer host immunity system regarding SARs-CoV-2 within a computational approach, concluding SARS-CoV2 may manipulate this system of immunity against its host, requiring further research. Mu et al., 2020 suggest SARs-CoV2 suppresses RNAi thus preventing recognition by the encoded ribonuclease dicer protein Viral suppressors of RNA silencing (VSRs) suppress RNAi at pre or post-dicer level to overcome host defense and establish infection. Cui et al. (2015) from Wuhan University laboratory of virology, identified a novel VSR from coronaviruses (CoVs) including Severe acute respiratory syndrome coronavirus (SARS-CoV) and showed that the coronavirus nucelocaspid protein (N-protein), conserved and expressed in all coronaviruses, suppressed RNAi triggered by either short hairpin RNAs or small interfering RNAs in mammalian cells. They went on to show using mouse hepatitis virus A-59 (MHV-A59) which is closely linked to SARS-CoV in the family coronaviridae, that the viral replication was increased when the N proteins (novel VSR) were expressed but that knockdown of DICER1 gene or Ago2 transcripts facilitated the viral replication specifically in mammalian cells. They demonstrate that the N-protein of CoVs could efficiently inhibit dicer-mediated dsRNA cleavage and post-Dicer activities by sequestering dsRNAs and siRNAs. Kannan et al. (2020) performed clustal W analysis of N-Protein for SARS-CoV and COVID-19 demonstrating 90% sequence identity from an NCBI amino acid blast of both nucleocapsid (N) protein sequences (figure2). They suggest that the N-protein of COVID-19 may also function as a VSR for RNAi to overcome host defense. Ding et al. (2017) show that both MHV and SARS-CoV N proteins can also disrupt protein activator of protein kinase R (PACT), a cellular dsRNA-binding protein which binds to RIG-I and MDA5 to activate interferon (IFN) production to prevent antiviral host response. Literature Review PMID: 17181864: Bennasser and Jeang, 2006 • HIV-1 Tat Interaction With Dicer: Requirement for RNA • Tat-Dicer interaction depends on RNA, requires the helicase domain of Dicer, and is independent of Tat's transactivation domain. PMID: 18325616: Chen et al., 2008 • HCV Core Protein Interacts With Dicer to Antagonize RNA Silencing PMID: 26085159: Cui et al., 2015 • The Nucleocapsid Protein of Coronaviruses Acts as a Viral Suppressor of RNA Silencing in Mammalian Cells PMID: 24303839: Devasthanam et al, 2014 • This study investigates the role of the dicer protein in immune cell development and function using dicer1 cre-lox knockout models to conditionally ablate dicer1 in different immune cell subsets. PMID: 28591694: Ding et al., 2017 • The nucleocapsid proteins of mouse hepatitis virus and severe acute respiratory syndrome coronavirus share the same IFN-β antagonizing mechanism: attenuation of PACT-mediated RIG-I/MDA5 activation PMID: 30015086: Ding et al., 2018 • Antiviral RNA Interference in Mammals: Indicates infection of plants and insects with RNA and DNA viruses triggers Dicer-dependent production of virus-derived small interfering RNAs (vsiRNAs), which subsequently guide specific virus clearance by RNA interference (RNAi). PMID: 25176334: Foulkes et al., 2012-REVIEW • Review of DICER1: DICER1 Mutations, microRNAs and Mechanisms PMID: 16554838: Galiana-Arnoux et al., 2006 • Essential function in vivo for Dicer-2 in host defense against RNA viruses in drosophila. • https://pubmed.ncbi.nlm.nih.gov/16554838/ or https://www.nature.com/articles/ni1335 PMID: 21385408: Inchley et al., 2011 • Investigates ribonuclease Dicer and analyzed the gene expression of Dicer in newborns of which 37 infants had sufficient cord blood RNA with confirmed RSV disease <1yr. Demonstrates significant reduced Dicer expression in cord blood prior to severe disease in infants <1yr later. Conclude downregulation may predispose infants to RSV disease. PMID: 32141569: Kannan et al., 2020 • COVID-19 (Novel Coronavirus 2019) - Recent Trends • Perform W cluster analysis of COVID-19 and SARS-CoV nucleocapsid (N) protein sequences of the viruses showing 90% amino acid sequence similarity. Suggest the N-protein may be a VSR in RNAi by targeting DICER. PMID: 23849790: Klockow et al., 2013 • The HIV-1 Protein Vpr Targets the Endoribonuclease Dicer for Proteasomal Degradation to Boost Macrophage Infection PMID: 25883138: Kurzynska-Kokorniak et al., 2015 • Investigating the complexity of the mechanisms regulating Dicer gene expression and enzyme activities PMID: 24115437: Li et al, 2013 • Investigates RNA interference pathways in antiviral immunity in mammals overviewing dicer processing of dsRNA viral replication intermediates into siRNAs. PMID: 27273616: Machitani et al., 2016 • Dicer functions as an antiviral system against human adenoviruses via cleavage of adenovirus-encoded noncoding RNA PMID: 30872283: Maillard et al., 2019- REVIEW • Reviewing DICER1 within the anti-viral RNAi pathway in mammals PMID: 30682089: Modai et al, 2019 • HIV-1 infection increases miRNAs which inhibit Dicer PMID: 32291557: Mu et al, 2020 • SARS-CoV-2-encoded nucleocapsid protein acts as a viral suppressor of RNA interference in cells PMID: 16009718: Muljo et al., 2005 • Indicates absence of dicer results in abberant T-cell differentiation. PMID: 17613256: Otsuka, et al 2007 • Hypersusceptibility to Vesicular Stomatitis Virus Infection in Dicer1-Deficient Mice Is Due to Impaired miR24 and miR93 Expression No PMID: Preprint : Pasquier and Rubichon, 2020 • SARS-CoV-2 might manipulate against its host the immunity RNAi/Dicer/Ago system PMID: 22438534: Qi et al., 2012 • Targeting of Dicer-2 and RNA by a Viral RNA Silencing Suppressor in Drosophila Cells PMID: 28473628: Song and Rossi, 2017 • Molecular Mechanisms of Dicer: Endonuclease and Enzymatic Activity; to: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): The DICER1 gene, located on chromosome 14, position q32.13, was discovered in 2001 by Bernstein and is a member of the RNase III family, (also known as dicer 1, ribonuclease III; dicer1, Dcr-1 homolog (Drosophila); multinodular goitre 1). DICER1 is involved in the generation of double-stranded microRNAs (miRNAs), short non-coding RNAs, the cleavage of dsRNA into siRNAs, along with the biogenesis of numerous other small RNAs. There is increasing evidence DICER1 is also involved in regulating many other essential cellular processes such as those related to chromatin remodeling, inflammation, apoptosis and cell survival (Kurzynska-Kokorniak et al. 2015; Song and Rossi, 2017). DICER1 encodes a ∼220-KDa protein (RNase III endoribonuclease) which is a crucial component of the RNA Induced Silencing Complex (RISC) loading complex (RLC), comprised of dicer, Argonaute-2 (AGO-2), and trans-activation-responsive RNA binding protein 2 (TARBP2). The encoded protein is required by the RNA interference (RNAi) and small temporal RNA (stRNA) pathways to produce the active small RNA component which has a role in modulating gene expression at the post-transcriptional level. Research has shown that expression levels of cellular transcript and protein dicer are strictly controlled, with aberrant regulation contributing to carcinogenesis, neurodegenerative, rheumatic and immune system disorders. Studies have concluded that the encoded dicer ribonuclease-dependent processing of dsRNA viral replication intermediates into successive siRNAs is a conserved mammalian immune response to infection by positive-strand RNA viruses (Svobodova et al. 2016 summary & fig1; Li et al. 2013; Ding et al. 2018). Moreover, miRNAs play an important role in host-virus interactions in mammals (See Maillard et al. 2019 REVIEW; Foulkes et al. 2014 REVIEW). IMMUNE SYSTEM The cre-lox method for dicer1 gene knockout has been employed for studies into the role of dicer1 in immune cell development and function. Studies of dicer1 fl/fl mice have indicated short survival times along with severely impaired GMP differentiation into monocytes, neutrophils, myeloid DCs & mature macrophages. (Devasthanam et al. 2014). Results conclude that dicer1 is important in immune response and also vital for cell survival and apoptosis pathways. Muljo et al. (2005) investigated a conditional allele of dicer-1 (dcr-1) within a mouse model and showed that specific dcr-1 deletion in the T-cell lineage, resulted in impaired development of T-cells & aberrant cell differentiation of T-helper cells & cytokine production. Dcr-1 deletion in the thymus resulted in severe block in development of CD8+ T cells and resulted in defective microRNA processing in CD4+ T-cells. The results demonstrate Dicer regulates diverse aspects of T-cell biology along with cytokine production during T-cell differentiation where dicer-deficient T-cells preferentially express interferon-ƴ. VIRUSES Research by Galiana-Arnoux et al. (2006), of DICER in drosophila (drosophila have two dicer genes) have identified that DICER genes (Dcr1, miRNA pathway and Dcr2, RNAi pathway) control production of siRNA and a loss-of-function mutation in Dcr2 resulted in increased susceptibility to three different families of RNA viruses. Qi et al. (2012) research into RNAi gene silencing mechanism show that the B2 protein in Wuhan nodavirus (WhNV) suppresses Dcr2 in drosophila by direct interaction with the PAZ and RNAse III domains therefore blocking processing of dsRNA and siRNA. Evidence of a dicer antiviral system was also reported by Machitani et al. (2016) for mammalian human adenoviruses where DICER1 gene knockdown increased the copy number of adenovirus-encoding small RNAs (VA-RNAs) leading to the promotion of adenovirus replication; conversely, dicer overexpression significantly inhibited viral replication. Modai et al. (2019) conclude that HIV-1 infection inhibits DICER1 by altering miRNA expression. They conclude that upon HIV-1 infection, human miR-186, 210 and 222 directly regulate DICER1 gene expression causing down-regulation of the gene contributing to impaired cell-mediated immunity (fig6). Other methods of inhibition are from viral proteins, termed viral suppressors of RNA silencing, which interact and inhibit dicer ribonuclease activity in HIV-1 and hepatitis C infections. These viral proteins may mediate proteasomal degradation of endoribonuclease dicer through CRL4DCAF1 ubiquitin ligase complex (Klockow et al. 2013), interact directly via the core protein (Chen et al. 2008) or HIV-1 transactivation of transcription (Bennasser and Jeang, 2006). Through these methods they can block dicer interactions with TRBP2 or ADAR1, boost macrophage infection, and subsequently reduce the function of short hairpin RNAs (shRNAs) which thus inhibit RNA silencing. Ultimately these viruses, though various methods, supress the ability of dicer to process dsRNAs into siRNAs boosting viral infection and pathogenesis. Downregulation of DICER1 gene expression has additionally been found in cord blood of infants with severe respiratory syncytial virus (RSV), prior to RSV exposure, indicating this reduced expression may predispose newborns to RSV disease. Inchley et al. (2011) theorize that this occurs via disruption of leukocyte gene regulation of miRNA and direct anti-viral RNAi mechanisms. (Inchley et al. 2011 see section on “Dicer Gene Expression”). Otsuka et al. (2007) have shown using gene-trap methods to obtain viable dicer1 fl/fl mice where dicer1 deficiency caused impairment of miR24 and miR93 production resulting in susceptibility to vesticular stomatitis virus (VSV) and herpes simplex-1 virus, but not other viruses tested. SARS CoV & SARS CoV-2 Recently, Pasquier and Robichon, 2020 (preprint) have investigated the Dicer host immunity system regarding SARs-CoV-2 within a computational approach, concluding SARS-CoV2 may manipulate this system of immunity against its host, requiring further research. Mu et al., 2020 suggest SARs-CoV2 suppresses RNAi thus preventing recognition by the encoded ribonuclease dicer protein Viral suppressors of RNA silencing (VSRs) suppress RNAi at pre or post-dicer level to overcome host defense and establish infection. Cui et al. (2015) from Wuhan University laboratory of virology, identified a novel VSR from coronaviruses (CoVs) including Severe acute respiratory syndrome coronavirus (SARS-CoV) and showed that the coronavirus nucelocaspid protein (N-protein), conserved and expressed in all coronaviruses, suppressed RNAi triggered by either short hairpin RNAs or small interfering RNAs in mammalian cells. They went on to show using mouse hepatitis virus A-59 (MHV-A59) which is closely linked to SARS-CoV in the family coronaviridae, that the viral replication was increased when the N proteins (novel VSR) were expressed but that knockdown of DICER1 gene or Ago2 transcripts facilitated the viral replication specifically in mammalian cells. They demonstrate that the N-protein of CoVs could efficiently inhibit dicer-mediated dsRNA cleavage and post-Dicer activities by sequestering dsRNAs and siRNAs. Kannan et al. (2020) performed clustal W analysis of N-Protein for SARS-CoV and COVID-19 demonstrating 90% sequence identity from an NCBI amino acid blast of both nucleocapsid (N) protein sequences (figure2). They suggest that the N-protein of COVID-19 may also function as a VSR for RNAi to overcome host defense. Ding et al. (2017) show that both MHV and SARS-CoV N proteins can also disrupt protein activator of protein kinase R (PACT), a cellular dsRNA-binding protein which binds to RIG-I and MDA5 to activate interferon (IFN) production to prevent antiviral host response. Literature Review PMID: 17181864: Bennasser and Jeang, 2006 • HIV-1 Tat Interaction With Dicer: Requirement for RNA • Tat-Dicer interaction depends on RNA, requires the helicase domain of Dicer, and is independent of Tat's transactivation domain. PMID: 18325616: Chen et al., 2008 • HCV Core Protein Interacts With Dicer to Antagonize RNA Silencing PMID: 26085159: Cui et al., 2015 • The Nucleocapsid Protein of Coronaviruses Acts as a Viral Suppressor of RNA Silencing in Mammalian Cells PMID: 24303839: Devasthanam et al, 2014 • This study investigates the role of the dicer protein in immune cell development and function using dicer1 cre-lox knockout models to conditionally ablate dicer1 in different immune cell subsets. PMID: 28591694: Ding et al., 2017 • The nucleocapsid proteins of mouse hepatitis virus and severe acute respiratory syndrome coronavirus share the same IFN-β antagonizing mechanism: attenuation of PACT-mediated RIG-I/MDA5 activation PMID: 30015086: Ding et al., 2018 • Antiviral RNA Interference in Mammals: Indicates infection of plants and insects with RNA and DNA viruses triggers Dicer-dependent production of virus-derived small interfering RNAs (vsiRNAs), which subsequently guide specific virus clearance by RNA interference (RNAi). PMID: 25176334: Foulkes et al., 2012-REVIEW • Review of DICER1: DICER1 Mutations, microRNAs and Mechanisms PMID: 16554838: Galiana-Arnoux et al., 2006 • Essential function in vivo for Dicer-2 in host defense against RNA viruses in drosophila. • https://pubmed.ncbi.nlm.nih.gov/16554838/ or https://www.nature.com/articles/ni1335 PMID: 21385408: Inchley et al., 2011 • Investigates ribonuclease Dicer and analyzed the gene expression of Dicer in newborns of which 37 infants had sufficient cord blood RNA with confirmed RSV disease <1yr. Demonstrates significant reduced Dicer expression in cord blood prior to severe disease in infants <1yr later. Conclude downregulation may predispose infants to RSV disease. PMID: 32141569: Kannan et al., 2020 • COVID-19 (Novel Coronavirus 2019) - Recent Trends • Perform W cluster analysis of COVID-19 and SARS-CoV nucleocapsid (N) protein sequences of the viruses showing 90% amino acid sequence similarity. Suggest the N-protein may be a VSR in RNAi by targeting DICER. PMID: 23849790: Klockow et al., 2013 • The HIV-1 Protein Vpr Targets the Endoribonuclease Dicer for Proteasomal Degradation to Boost Macrophage Infection PMID: 25883138: Kurzynska-Kokorniak et al., 2015 • Investigating the complexity of the mechanisms regulating Dicer gene expression and enzyme activities PMID: 24115437: Li et al, 2013 • Investigates RNA interference pathways in antiviral immunity in mammals overviewing dicer processing of dsRNA viral replication intermediates into siRNAs. PMID: 27273616: Machitani et al., 2016 • Dicer functions as an antiviral system against human adenoviruses via cleavage of adenovirus-encoded noncoding RNA PMID: 30872283: Maillard et al., 2019- REVIEW • Reviewing DICER1 within the anti-viral RNAi pathway in mammals PMID: 30682089: Modai et al, 2019 • HIV-1 infection increases miRNAs which inhibit Dicer PMID: 32291557: Mu et al, 2020 • SARS-CoV-2-encoded nucleocapsid protein acts as a viral suppressor of RNA interference in cells PMID: 16009718: Muljo et al., 2005 • Indicates absence of dicer results in abberant T-cell differentiation. PMID: 17613256: Otsuka, et al 2007 • Hypersusceptibility to Vesicular Stomatitis Virus Infection in Dicer1-Deficient Mice Is Due to Impaired miR24 and miR93 Expression No PMID: Preprint : Pasquier and Rubichon, 2020 • SARS-CoV-2 might manipulate against its host the immunity RNAi/Dicer/Ago system PMID: 22438534: Qi et al., 2012 • Targeting of Dicer-2 and RNA by a Viral RNA Silencing Suppressor in Drosophila Cells PMID: 28473628: Song and Rossi, 2017 • Molecular Mechanisms of Dicer: Endonuclease and Enzymatic Activity |
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| COVID-19 research v0.348 | DICER1 |
Rebecca Foulger commented on gene: DICER1: Evidence Summary from Illumina curation team: The DICER1 gene, located on chromosome 14, position q32.13, was discovered in 2001 by Bernstein and is a member of the RNase III family, (also known as dicer 1, ribonuclease III; dicer1, Dcr-1 homolog (Drosophila); multinodular goitre 1). DICER1 is involved in the generation of double-stranded microRNAs (miRNAs), short non-coding RNAs, the cleavage of dsRNA into siRNAs, along with the biogenesis of numerous other small RNAs. There is increasing evidence DICER1 is also involved in regulating many other essential cellular processes such as those related to chromatin remodeling, inflammation, apoptosis and cell survival (Kurzynska-Kokorniak et al. 2015; Song and Rossi, 2017). DICER1 encodes a ∼220-KDa protein (RNase III endoribonuclease) which is a crucial component of the RNA Induced Silencing Complex (RISC) loading complex (RLC), comprised of dicer, Argonaute-2 (AGO-2), and trans-activation-responsive RNA binding protein 2 (TARBP2). The encoded protein is required by the RNA interference (RNAi) and small temporal RNA (stRNA) pathways to produce the active small RNA component which has a role in modulating gene expression at the post-transcriptional level. Research has shown that expression levels of cellular transcript and protein dicer are strictly controlled, with aberrant regulation contributing to carcinogenesis, neurodegenerative, rheumatic and immune system disorders. Studies have concluded that the encoded dicer ribonuclease-dependent processing of dsRNA viral replication intermediates into successive siRNAs is a conserved mammalian immune response to infection by positive-strand RNA viruses (Svobodova et al. 2016 summary & fig1; Li et al. 2013; Ding et al. 2018). Moreover, miRNAs play an important role in host-virus interactions in mammals (See Maillard et al. 2019 REVIEW; Foulkes et al. 2014 REVIEW). IMMUNE SYSTEM The cre-lox method for dicer1 gene knockout has been employed for studies into the role of dicer1 in immune cell development and function. Studies of dicer1 fl/fl mice have indicated short survival times along with severely impaired GMP differentiation into monocytes, neutrophils, myeloid DCs & mature macrophages. (Devasthanam et al. 2014). Results conclude that dicer1 is important in immune response and also vital for cell survival and apoptosis pathways. Muljo et al. (2005) investigated a conditional allele of dicer-1 (dcr-1) within a mouse model and showed that specific dcr-1 deletion in the T-cell lineage, resulted in impaired development of T-cells & aberrant cell differentiation of T-helper cells & cytokine production. Dcr-1 deletion in the thymus resulted in severe block in development of CD8+ T cells and resulted in defective microRNA processing in CD4+ T-cells. The results demonstrate Dicer regulates diverse aspects of T-cell biology along with cytokine production during T-cell differentiation where dicer-deficient T-cells preferentially express interferon-ƴ. VIRUSES Research by Galiana-Arnoux et al. (2006), of DICER in drosophila (drosophila have two dicer genes) have identified that DICER genes (Dcr1, miRNA pathway and Dcr2, RNAi pathway) control production of siRNA and a loss-of-function mutation in Dcr2 resulted in increased susceptibility to three different families of RNA viruses. Qi et al. (2012) research into RNAi gene silencing mechanism show that the B2 protein in Wuhan nodavirus (WhNV) suppresses Dcr2 in drosophila by direct interaction with the PAZ and RNAse III domains therefore blocking processing of dsRNA and siRNA. Evidence of a dicer antiviral system was also reported by Machitani et al. (2016) for mammalian human adenoviruses where DICER1 gene knockdown increased the copy number of adenovirus-encoding small RNAs (VA-RNAs) leading to the promotion of adenovirus replication; conversely, dicer overexpression significantly inhibited viral replication. Modai et al. (2019) conclude that HIV-1 infection inhibits DICER1 by altering miRNA expression. They conclude that upon HIV-1 infection, human miR-186, 210 and 222 directly regulate DICER1 gene expression causing down-regulation of the gene contributing to impaired cell-mediated immunity (fig6). Other methods of inhibition are from viral proteins, termed viral suppressors of RNA silencing, which interact and inhibit dicer ribonuclease activity in HIV-1 and hepatitis C infections. These viral proteins may mediate proteasomal degradation of endoribonuclease dicer through CRL4DCAF1 ubiquitin ligase complex (Klockow et al. 2013), interact directly via the core protein (Chen et al. 2008) or HIV-1 transactivation of transcription (Bennasser and Jeang, 2006). Through these methods they can block dicer interactions with TRBP2 or ADAR1, boost macrophage infection, and subsequently reduce the function of short hairpin RNAs (shRNAs) which thus inhibit RNA silencing. Ultimately these viruses, though various methods, supress the ability of dicer to process dsRNAs into siRNAs boosting viral infection and pathogenesis. Downregulation of DICER1 gene expression has additionally been found in cord blood of infants with severe respiratory syncytial virus (RSV), prior to RSV exposure, indicating this reduced expression may predispose newborns to RSV disease. Inchley et al. (2011) theorize that this occurs via disruption of leukocyte gene regulation of miRNA and direct anti-viral RNAi mechanisms. (Inchley et al. 2011 see section on “Dicer Gene Expression”). Otsuka et al. (2007) have shown using gene-trap methods to obtain viable dicer1 fl/fl mice where dicer1 deficiency caused impairment of miR24 and miR93 production resulting in susceptibility to vesticular stomatitis virus (VSV) and herpes simplex-1 virus, but not other viruses tested. SARS CoV & SARS CoV-2 Recently, Pasquier and Robichon, 2020 (preprint) have investigated the Dicer host immunity system regarding SARs-CoV-2 within a computational approach, concluding SARS-CoV2 may manipulate this system of immunity against its host, requiring further research. Mu et al., 2020 suggest SARs-CoV2 suppresses RNAi thus preventing recognition by the encoded ribonuclease dicer protein Viral suppressors of RNA silencing (VSRs) suppress RNAi at pre or post-dicer level to overcome host defense and establish infection. Cui et al. (2015) from Wuhan University laboratory of virology, identified a novel VSR from coronaviruses (CoVs) including Severe acute respiratory syndrome coronavirus (SARS-CoV) and showed that the coronavirus nucelocaspid protein (N-protein), conserved and expressed in all coronaviruses, suppressed RNAi triggered by either short hairpin RNAs or small interfering RNAs in mammalian cells. They went on to show using mouse hepatitis virus A-59 (MHV-A59) which is closely linked to SARS-CoV in the family coronaviridae, that the viral replication was increased when the N proteins (novel VSR) were expressed but that knockdown of DICER1 gene or Ago2 transcripts facilitated the viral replication specifically in mammalian cells. They demonstrate that the N-protein of CoVs could efficiently inhibit dicer-mediated dsRNA cleavage and post-Dicer activities by sequestering dsRNAs and siRNAs. Kannan et al. (2020) performed clustal W analysis of N-Protein for SARS-CoV and COVID-19 demonstrating 90% sequence identity from an NCBI amino acid blast of both nucleocapsid (N) protein sequences (figure2). They suggest that the N-protein of COVID-19 may also function as a VSR for RNAi to overcome host defense. Ding et al. (2017) show that both MHV and SARS-CoV N proteins can also disrupt protein activator of protein kinase R (PACT), a cellular dsRNA-binding protein which binds to RIG-I and MDA5 to activate interferon (IFN) production to prevent antiviral host response. Literature Review PMID: 17181864: Bennasser and Jeang, 2006 • HIV-1 Tat Interaction With Dicer: Requirement for RNA • Tat-Dicer interaction depends on RNA, requires the helicase domain of Dicer, and is independent of Tat's transactivation domain. PMID: 18325616: Chen et al., 2008 • HCV Core Protein Interacts With Dicer to Antagonize RNA Silencing PMID: 26085159: Cui et al., 2015 • The Nucleocapsid Protein of Coronaviruses Acts as a Viral Suppressor of RNA Silencing in Mammalian Cells PMID: 24303839: Devasthanam et al, 2014 • This study investigates the role of the dicer protein in immune cell development and function using dicer1 cre-lox knockout models to conditionally ablate dicer1 in different immune cell subsets. PMID: 28591694: Ding et al., 2017 • The nucleocapsid proteins of mouse hepatitis virus and severe acute respiratory syndrome coronavirus share the same IFN-β antagonizing mechanism: attenuation of PACT-mediated RIG-I/MDA5 activation PMID: 30015086: Ding et al., 2018 • Antiviral RNA Interference in Mammals: Indicates infection of plants and insects with RNA and DNA viruses triggers Dicer-dependent production of virus-derived small interfering RNAs (vsiRNAs), which subsequently guide specific virus clearance by RNA interference (RNAi). PMID: 25176334: Foulkes et al., 2012-REVIEW • Review of DICER1: DICER1 Mutations, microRNAs and Mechanisms PMID: 16554838: Galiana-Arnoux et al., 2006 • Essential function in vivo for Dicer-2 in host defense against RNA viruses in drosophila. • https://pubmed.ncbi.nlm.nih.gov/16554838/ or https://www.nature.com/articles/ni1335 PMID: 21385408: Inchley et al., 2011 • Investigates ribonuclease Dicer and analyzed the gene expression of Dicer in newborns of which 37 infants had sufficient cord blood RNA with confirmed RSV disease <1yr. Demonstrates significant reduced Dicer expression in cord blood prior to severe disease in infants <1yr later. Conclude downregulation may predispose infants to RSV disease. PMID: 32141569: Kannan et al., 2020 • COVID-19 (Novel Coronavirus 2019) - Recent Trends • Perform W cluster analysis of COVID-19 and SARS-CoV nucleocapsid (N) protein sequences of the viruses showing 90% amino acid sequence similarity. Suggest the N-protein may be a VSR in RNAi by targeting DICER. PMID: 23849790: Klockow et al., 2013 • The HIV-1 Protein Vpr Targets the Endoribonuclease Dicer for Proteasomal Degradation to Boost Macrophage Infection PMID: 25883138: Kurzynska-Kokorniak et al., 2015 • Investigating the complexity of the mechanisms regulating Dicer gene expression and enzyme activities PMID: 24115437: Li et al, 2013 • Investigates RNA interference pathways in antiviral immunity in mammals overviewing dicer processing of dsRNA viral replication intermediates into siRNAs. PMID: 27273616: Machitani et al., 2016 • Dicer functions as an antiviral system against human adenoviruses via cleavage of adenovirus-encoded noncoding RNA PMID: 30872283: Maillard et al., 2019- REVIEW • Reviewing DICER1 within the anti-viral RNAi pathway in mammals PMID: 30682089: Modai et al, 2019 • HIV-1 infection increases miRNAs which inhibit Dicer PMID: 32291557: Mu et al, 2020 • SARS-CoV-2-encoded nucleocapsid protein acts as a viral suppressor of RNA interference in cells PMID: 16009718: Muljo et al., 2005 • Indicates absence of dicer results in abberant T-cell differentiation. PMID: 17613256: Otsuka, et al 2007 • Hypersusceptibility to Vesicular Stomatitis Virus Infection in Dicer1-Deficient Mice Is Due to Impaired miR24 and miR93 Expression No PMID: Preprint : Pasquier and Rubichon, 2020 • SARS-CoV-2 might manipulate against its host the immunity RNAi/Dicer/Ago system PMID: 22438534: Qi et al., 2012 • Targeting of Dicer-2 and RNA by a Viral RNA Silencing Suppressor in Drosophila Cells PMID: 28473628: Song and Rossi, 2017 • Molecular Mechanisms of Dicer: Endonuclease and Enzymatic Activity |
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| COVID-19 research v0.347 | IRF1 | Julie Taylor commented on gene: IRF1: Evidence Summary from Illumina curation team: IRF1 encodes interferon regulatory factor 1, a member of the family of transcription factors that play a role in regulating both the innate and adaptive immune response. IRF1 is constitutively expressed at a low level but significantly elevated upon IFN-I stimulation, elevated IRF1 further amplifies the IFN response through a positive feedback loop (Lukele et al. 2019, Review). IRF-1 attenuates the replication of several viruses, including hepatitis C virus, West Nile virus (WNV), and EMCV, (Schoggins et al 2011) and IRF1 knock out mice are more susceptible to some viruses, such as EMCV and coxsackievirus B3, than wild type mice (Kimura et al. 1994). Using an IRF1 deficient BEAS2B bronchial epithelial cell line with increased susceptibility to VSV, and multiple strains of influenza viruses, Panda et al. 2019, showed that IRF1 is important for the early expression of types I and III IFNs and ISGs. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.347 | DEFA1 | Alison Coffey commented on gene: DEFA1: Evidence Summary from Illumina curation team: DEFA1, or HNP1, is a member of the defensin family of host defense peptides, a group of microbicidal and cytotoxic peptides made by neutrophils. Defensins are known to have a role in innate immunity as a core host-protective component against bacterial, viral and fungal infections (Xu and Wuyaun, 2020). Defensins have direct antiviral activity in cell culture, with varied mechanisms for individual viruses. Defensins also have a potent immunomodulatory activity that can alter innate and adaptive immune responses to viral infection and are able to target multiple steps of host-virus interactions to reduce infectivity of both enveloped and non-enveloped viruses. Targets include viral envelopes, glycoproteins, and capsids or host cells. DEFA1 is well-recognized for its direct anti-HIV activity, it also restrains HIV-1 uptake by inhibiting Env-mediated viral fusion and downregulating host cell surface expression of CD4 and coreceptor CXCR4. Post-entry inhibition of enveloped viruses such as HIV-1 and influenza by DEFA1 is mediated through interfering with cell signaling pathways such as PKC that are required for viral replication (Xu and Wuyaun, 2020). An unpublished study by Kit and Kit (2020), demonstrated in silico that the affinity of human alpha-defensins 1, 2, 3 and 5 to SARS-CoV-2 spike protein is higher than that of the SARS-CoV-2 spike protein towards ACE2. The authors suggest that these alpha-defensins may serve as primary factors in protecting lung tissue from COVID-19 viral infection. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.347 | CXADR | Alison Coffey commented on gene: CXADR: Evidence Summary from Illumina curation team: The coxsackie and adenovirus receptor (CXADR or CAR), also known as CAR-like membrane protein (CLMP), was first identified as a high affinity receptor for adenovirus serotypes 2 and 5 and coxsackie viruses group B. CXADR is developmentally regulated and plays an important role in cardiac development. The protein is a transmembrane receptor and plays a key role in controlling adhesion between adjacent epithelial cells. It is also implicated in controlling both recruitment of immune cells and in tumorigenesis (Zapater et al. 2017). Vehik et al. (2018) concluded that a SNP within the CXADR region is associated with islet autoimmunity. In response to exogenous TNF?, CAR promotes transmigration of leukocytes both in vitro and in vivo. suggesting that CAR may be an important receptor in the control of inflammation. As neutrophils and T cells play a role in host immunity, these data suggest that CAR may be ideally positioned to modulate the immune response from the epithelial or endothelial cell compartments. (Morton et al 2016). CAR expression and infectivity with adenovirus (Ad) are increased in cystic fibrosis airway epithelial cells (Sharma et al. 2017). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.347 | VPS33A | Alison Coffey commented on gene: VPS33A: Evidence Summary from Illumina curation team: VPS33A is a member of the Sec1/Munc18-related (SM) protein family and a core component of the class C core vacuole/endosome tethering (CORVET) and the homotypic fusion and protein sorting (HOPS) complexes (Vasilev et al. 2020). Both complexes are heterohexamers and share four subunits. VPS33A, VPS11, VPS16 and VPS18, involved in endolysosomal pathway. Deficiency of VPS33A was shown to affect susceptibility to certain viruses in cell culture, including Ebola and Marburg viruses (Carette et al. 2011), however no human studies confirming this association were identified. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.347 | ITGAV | Alison Coffey commented on gene: ITGAV: Evidence Summary from Illumina curation team: ITGAV or ALPHA-V is a component of the integrin family of transmembrane proteins. Integrins primary biological functions involve cell adhesion and migration, organization of the cytoskeleton, and other cellular functions. Alpha-V-containing integrins combine an alpha-V subunit with 1 of 5 beta subunits. Several families of viruses are known to use alpha-V-containing integrins for cell attachment and entry, including human adenovirus type 2/5, human CMV, HIV-1, EBV, rotavirus, Coxsackievirus, and Ebola virus (Hussein et al. 2015; LaFoya et al. 2018). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.347 | IL9 | Alison Coffey commented on gene: IL9: Evidence Summary from Illumina curation team: IL9 encodes interleukin 9, which is a stimulatory cytokine that regulates inflammatory immunity (Goswami and Kaplan 2011). It has been demonstrated that high levels of IL-9 are present in nasopharyngeal aspirate of infants with disease of the respiratory tract caused by the Human respiratory syncytial virus (RSV) (Semple et al. 2007). Studies conducted on mice showed that that the severity of lung pathology correlates with IL-9 cytokine production and that Th9 cells, which produce IL-9, play an important role in the development of airway eosinophilia and bronchial hyperresponsiveness (Dodd et al. 2009; Saeki et al. 2016). IL9 polymorphisms have also been linked to sex-restricted differences in lung function, allergen sensitization, IgE levels, and the severity of respiratory syncytial virus infection (Schuurhof et al. 2010; Aschard et al. 2009). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.347 | CCR7 | Alison Coffey commented on gene: CCR7: Evidence Summary from Illumina curation team: The CCR7 gene encodes the C-C chemokine receptor 7, a chemokine receptor which is a member of the G protein-coupled receptor superfamily. CCR7 plays an important role in the homing of central memory and nave T cells to peripheral lymphoid organs. The binding of CCR7 ligands CCL19 and CCL21 during viral infection promotes activation and differentiation of CCR7 expressing cells, as well as changes in their migration properties to modulate the immune response (reviewed Yan et al. 2019). Some viral proteins target CCR7 and reduce its expression during viral infection (reviewed Yan et al. 2019), for example, the HIV-1 accessory protein, Vpu, interacts directly with CCR7 to cause its retention within the trans Golgi network of primary CD4+ T cells (Ramirez et al. 2014). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.347 | ATG5 | Alison Coffey commented on gene: ATG5: Evidence Summary from Illumina curation team: The ATG5 gene encodes a core autophagy protein which forms a complex with ATG12 and ATG16L that is important for autophagophore elongation. Autophagy plays a key antiviral role in various human infections by modulating different aspects of the immune response (Reviewed Tao et al. 2020; Ahmed et al.2018). ATG5 may play a role in cytokine regulation, in vitro, ATG5 depleted primary human blood macrophages produced lower levels of CXCL10 and IFNa when infected with influenza A virus (Law et al. 2007). ATG5 deficient mice also show reduced Ifn and Il22 secretion when infected with the single stranded RNA vesicular stomatitis virus (VSV) (Lee et al. 2007). Using a mouse model with a conditional depletion of ATG5 within dendritic cells, Lee et al. 2010 showed that ATG5 is required for antigen presentation by dendritic cells, as a result of reduced MHC-II antigen presentation, these mice, when intradermally injected with HSV-1, showed significantly lower IFNgamma production by CD4+ T cells. (Lee et al., 2010). The ATG5 complex is targeted by some viruses to enhance infection, for example, the foot and mouth disease virus (FMDV) targets the ATG5-ATG12 complex for degradation through its viral protein 3Cpro, similarly, depletion of ATG5 and ATG12 in vitro, by siRNA increased susceptibility to FMDV infection by reducing activation of the NF-?B and IRF3 pathways (Fan et al 2017). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.347 | ATG16L1 | Alison Coffey commented on gene: ATG16L1: Evidence Summary from Illumina curation team: The ATG16L gene encodes a core autophagy protein which forms a complex with ATG5 and ATG12 that is important for autophagophore elongation (Lavoie et al. 2019). Autophagy plays a key antiviral role in various human infections by modulating different aspects of the immune response (Reviewed Tao et al. 2020; Ahmed et al. 2018). The ATG16L complex is also targeted by some viruses to enhance infection. The Zika virus protease, targets ATG16L, dramatically depleting its levels during Zika virus infection (Hill et al. 2018). Conversely, Hepatitis B virus (HBV), an enveloped pararetrovirus, stimulates autophagy to favor its production. In vitro, RNA interference-mediated silencing of Atg16L1 interfered with viral core/nucleocapsid (NC) formation and stability, strongly diminishing virus replication (Fletcher et al. 2018). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.299 | MUC5B |
Eleanor Williams gene: MUC5B was added gene: MUC5B was added to COVID-19 research. Sources: Literature Mode of inheritance for gene: MUC5B was set to Unknown Review for gene: MUC5B was set to RED Added comment: Preprint: van Moorsel et al https://doi.org/10.1101/2020.05.12.20099333 The mucin MUC5B is an important component of the innate immune response and expression levels are associated with the MUC5B promoter polymorphism, rs35705950. They compared patients with severe COVID-19 to controls and found the MUC5B rs35705950 promoter polymorphism associates with COVID-19. The risk allele (T) for idiopathic pulmonary fibrosis (IPF) is protective against the development of severe COVID-19 disease. Sources: Literature |
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| COVID-19 research v0.296 | PYCARD |
Eleanor Williams gene: PYCARD was added gene: PYCARD was added to COVID-19 research. Sources: Literature Mode of inheritance for gene: PYCARD was set to Unknown Publications for gene: PYCARD were set to 18288107 Review for gene: PYCARD was set to RED Added comment: Not associated with a disease phenotype in OMIM. PYCARD is also known as ASC PMID: 18288107 Muruve et al. 2008 - internalized adenoviral DNA induces maturation of pro-IL1B in macrophages, which is dependent on NALP3 and ASC, components of the innate cytosolic molecular complex termed the inflammasome. ASC-deficient mice display reduced innate inflammatory responses to adenovirus particles. Sources: Literature |
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| COVID-19 research v0.213 | KPNA2 |
Rebecca Foulger changed review comment from: KPNA2 present in the UniProt COVID portal (11th May 2020 Release): https://covid-19.uniprot.org/uniprotkb/P52292. KPNA2 acts as a nuclear import factor. KPNA2 is retained in ER/Golgi membranes upon interaction with SARS-COV virus ORF6 protein, and therefore KPNA2 is unable to transport STAT1 into the nucleus, therby blocking the expression of STAT1-activated genes that establish an antiviral state (PMID:17596301). Sources: Literature, Other; to: KPNA2 is present in the UniProt COVID portal (11th May 2020 Release): https://covid-19.uniprot.org/uniprotkb/P52292. KPNA2 acts as a nuclear import factor. KPNA2 is retained in ER/Golgi membranes upon interaction with SARS-COV virus ORF6 protein, and therefore KPNA2 is unable to transport STAT1 into the nucleus, therby blocking the expression of STAT1-activated genes that establish an antiviral state (PMID:17596301). Sources: Literature, Other |
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| COVID-19 research v0.213 | KPNA2 |
Rebecca Foulger gene: KPNA2 was added gene: KPNA2 was added to Viral susceptibility. Sources: Literature,Other Mode of inheritance for gene: KPNA2 was set to Unknown Publications for gene: KPNA2 were set to 17596301 Added comment: KPNA2 present in the UniProt COVID portal (11th May 2020 Release): https://covid-19.uniprot.org/uniprotkb/P52292. KPNA2 acts as a nuclear import factor. KPNA2 is retained in ER/Golgi membranes upon interaction with SARS-COV virus ORF6 protein, and therefore KPNA2 is unable to transport STAT1 into the nucleus, therby blocking the expression of STAT1-activated genes that establish an antiviral state (PMID:17596301). Sources: Literature, Other |
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| COVID-19 research v0.204 | IL18 | Sophie Hambleton edited their review of gene: IL18: Added comment: IL-18 is important in the pathogenesis of HLH (PMID:29326099) and the newly described autoinflammatory state IL18PAP-MAS (PMID: 31874111). Elevated IL-18 levels were detected in patients with COVID although not differentiating severe from mild/moderate disease (MedRxiv preprint https://doi.org/10.1101/2020.03.02.20029975). It is plausible that genetically determined differences in the activity of IL-18 might influence risk of severe COVID-19; Changed rating: AMBER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.190 | CDC42 |
Ivone Leong gene: CDC42 was added gene: CDC42 was added to Viral susceptibility. Sources: Expert Review Mode of inheritance for gene: CDC42 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: CDC42 were set to 31601675; 32303876; 32231661; 31271789 Phenotypes for gene: CDC42 were set to Neonatal-onset cytopaenia with dyshaematopoiesis; autoinflammation; rash; HLH Review for gene: CDC42 was set to GREEN Added comment: "PMID 31601675: four unrelated individuals with superimposable features, including neonatal-onset cytopenia with dyshematopoiesis, autoinflammation, rash, and HLH. All shared the same de novo CDC42 variant (Chr1:22417990C>T, p.R186C). Another pair of sibs reported in PMID 32303876 with infantile myelofibrosis and myeloproliferation and same variant (parental mosaicism). Yet another individual in PMID 32231661 with different de novo variant, p.Cys81Tyr who in addition developed haematological malignancy and also had syndromic features, including ID. Note other missense variants in this gene cause Takenouchi-Kosaki syndrome, MIM# 616737 Sources: Literature Zornitza Stark (Australian Genomics), 30 Apr 2020" - review copied from Primary immunodeficiency (Version 2.153) "Comment on list classification: Gene added by Zornitza Stark (Australian Genomics) with a suggested Green rating based on evidence she has provided. As well as the listed cases there is another paper (PMID: 31271789) describing 4 unrelated cases with de novo variants in CDC42 (p.C188Y, p.R186C, p.*192C*24). The patients predominantly had systemic autoinflammatory disease and development of HLH. Therefore there is enough evidence to rate this gene as Green. Ivone Leong (Genomics England Curator), 5 May 2020" - review copied from Primary immunodeficiency (Version 2.153) Sources: Expert Review |
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| COVID-19 research v0.160 | TLR3 |
Abdelazeem Elhabyan changed review comment from: These studies demonstrate the deleterious effect of some TLR3 mutations and predisposition to Herpes simplex encephalitis in 4 separate studies on unrelated patients from different countries. TLR3 mutations in 3 children were associated with severe influenza pneumonitis. Finally, 2 other studies evaluate the protective effect of a common polymorphism of TLR3 against HIV infection in repetitively exposed individuals. Accordingly, we might find protective or deleterious effects in COVID19 patients due to different mutations of TLR3. TLR3 is a receptor for dsRNA (intermediate in the replication of many viruses including HSV) which induces IFN response to prevent the cytopathic effects of different viruses. A heterozygous dominant-negative mutation of TLR3 was discovered in 2 unrelated children with HSE. TLR3 mutant fibroblasts from the 2 patients were infected by HSV-1 and vesicular stomatitis virus(VSV).IFNB and IFNL production were impaired in those cells, viral replication was higher and cell survival was lower in the 2 patients' cells when compared with the controls. Blood leukocyte response normally with to poly (I:C) which explains why the disease is not disseminated and also explains the redundant role of TLR3 in blood cells(13). Similar findings were reported in a polish child in 2011, however, the patient here was compound heterozygous for a missense mutation leading to autosomal recessive inheritance of TLR3 deficiency(14). Treatment with IFN alpha and beta canceled the effect of the dominant-negative mutation increasing the causality relationship between TLR3 mutants and viral immune response(13). Relatives of the 2 patients with the same mutation did not show decreased interferon response nor they showed HSE as a complication of HSV which means that this mutation does not have full penetrance(13). In another study, 110 patients with HSE were sequenced (exons of TLR3) to establish a new association of TLR3 mutations and HSE. The study reported 5 novel variants other than those previously described in the literature. 2 of them were not pathogenically demonstrated by in vitro studies while 3 of them were pathogenic with similar findings to those described above. Additionally, they found 3 patients with the same mutations previously described in the literature so the total of patients with deleterious TLR3 mutations would be 6 out of 110. 4 of those 6 patients(66%) with TLR6 mutations had a relapse In contrast to 12 out of 120(total cohort) (10%)(15). In a recent study done on 16 patients with adult-onset HSE using whole-exome sequencing(WES), 1 patient was discovered to have TLR3 deficiency, while 8 other patients had mutations in other genes in the TLR3 pathway(2 patients with a mutation in IRF3, 2 patients with mutations in STAT1, 2 patients with mutations in TRIF, 1 patient with a mutation in TYK2,1 patients with a mutation in MAVS, and finally 1 patient with a mutation in TBK1)(16) A common polymorphism in TLR3(rs3775291) was linked to increased resistance to HIV1 infection by the genotyping study of Spanish and Italian cohorts with a P value of .023 and .029 respectively. The study compared HIV exposed seronegative cohort(IV drug abuse and sexually active ) with controls. Repetitive HIV exposure in the cohort was evidenced by HCV seropositivity. In vitro infection of PBMCs with HIV showed increased resistance in cells carrying the allele and also TLR3 stimulation by TLR3 agonists showed an increased level of expression of CD69, IL-6, and CCL3(17). A similar study was conducted on the Caucasian population showing the protective effect of the allele against HIV infection(18). Autosomal recessive IRF7 and IRF9 deficiencies impair type I and III IFN immunity and underlie severe influenza pneumonitis. We report three unrelated children with influenza A virus (IAV) infection manifesting as acute respiratory distress syndrome (IAV-ARDS), heterozygous for rare TLR3 variants (P554S in two patients and P680L in the third) causing autosomal dominant (AD) TLR3 deficiency. AD TLR3 deficiency can underlie herpes simplex virus-1 (HSV-1) encephalitis (HSE) by impairing cortical neuron-intrinsic type I IFN immunity to HSV-1. TLR3-mutated leukocytes produce normal levels of IFNs in response to IAV. In contrast, TLR3-mutated fibroblasts produce lower levels of IFN-β and -λ, and display enhanced viral susceptibility, upon IAV infection. Moreover, the patients’ iPSC-derived pulmonary epithelial cells (PECs) are susceptible to IAV. Treatment with IFN-α2b or IFN-λ1 rescues this phenotype. AD TLR3 deficiency may thus underlie IAV-ARDS by impairing TLR3-dependent, type I, and/or III IFN–mediated, PEC-intrinsic immunity. Its clinical penetrance is incomplete for both IAV-ARDS and HSE, consistent with their typically sporadic nature(PMID: 31217193 ) 13.Zhang SY, Jouanguy E, Ugolini S, et al. TLR3 deficiency in patients with herpes simplex encephalitis. Science. 2007;317(5844):1522–1527. doi:10.1126/science.1139522 14.Guo Y, Audry M, Ciancanelli M, et al. Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency: TLR3 is otherwise redundant in protective immunity. J Exp Med. 2011;208(10):2083–2098. doi:10.1084/jem.20101568 15.Lim HK, Seppänen M, Hautala T, et al. TLR3 deficiency in herpes simplex encephalitis: high allelic heterogeneity and recurrence risk. Neurology. 2014;83(21):1888–1897. doi:10.1212/WNL.0000000000000999 16.Mørk N, Kofod-Olsen E, Sørensen KB, et al. Mutations in the TLR3 signaling pathway and beyond in adult patients with herpes simplex encephalitis. Genes Immun. 2015;16(8):552–566. doi:10.1038/gene.2015.46 17.Sironi M, Biasin M, Cagliani R, et al. A common polymorphism in TLR3 confers natural resistance to HIV-1 infection. J Immunol. 2012;188(2):818–823. doi:10.4049/jimmunol.1102179 18.Huik K, Avi R, Pauskar M, et al. Association between TLR3 rs3775291 and resistance to HIV among highly exposed Caucasian intravenous drug users. Infect Genet Evol. 2013;20:78–82. doi:10.1016/j.meegid.2013.08.008 19.Lim HK, Huang SXL, Chen J, et al. Severe influenza pneumonitis in children with inherited TLR3 deficiency. J Exp Med. 2019;216(9):2038–2056. doi:10.1084/jem.20181621; to: These studies demonstrate the deleterious effect of some TLR3 mutations and predisposition to Herpes simplex encephalitis in 4 separate studies on unrelated patients from different countries. TLR3 mutations in 3 children were associated with severe influenza pneumonitis. Finally, 2 other studies evaluate the protective effect of a common polymorphism of TLR3 against HIV infection in repetitively exposed individuals. Accordingly, we might find protective or deleterious effects in COVID19 patients due to different mutations of TLR3. TLR3 is a receptor for dsRNA (intermediate in the replication of many viruses including HSV) which induces IFN response to prevent the cytopathic effects of different viruses. A heterozygous dominant-negative mutation of TLR3 was discovered in 2 unrelated children with HSE. TLR3 mutant fibroblasts from the 2 patients were infected by HSV-1 and vesicular stomatitis virus(VSV).IFNB and IFNL production were impaired in those cells, viral replication was higher and cell survival was lower in the 2 patients' cells when compared with the controls. Blood leukocyte response normally with to poly (I:C) which explains why the disease is not disseminated and also explains the redundant role of TLR3 in blood cells(13). Similar findings were reported in a polish child in 2011, however, the patient here was compound heterozygous for a missense mutation leading to autosomal recessive inheritance of TLR3 deficiency(14). Treatment with IFN alpha and beta canceled the effect of the dominant-negative mutation increasing the causality relationship between TLR3 mutants and viral immune response(13). Relatives of the 2 patients with the same mutation did not show decreased interferon response nor they showed HSE as a complication of HSV which means that this mutation does not have full penetrance(13). In another study, 110 patients with HSE were sequenced (exons of TLR3) to establish a new association of TLR3 mutations and HSE. The study reported 5 novel variants other than those previously described in the literature. 2 of them were not pathogenically demonstrated by in vitro studies while 3 of them were pathogenic with similar findings to those described above. Additionally, they found 3 patients with the same mutations previously described in the literature so the total of patients with deleterious TLR3 mutations would be 6 out of 110. 4 of those 6 patients(66%) with TLR6 mutations had a relapse In contrast to 12 out of 120(total cohort) (10%)(15). In a recent study done on 16 patients with adult-onset HSE using whole-exome sequencing(WES), 1 patient was discovered to have TLR3 deficiency, while 8 other patients had mutations in other genes in the TLR3 pathway(2 patients with a mutation in IRF3, 2 patients with mutations in STAT1, 2 patients with mutations in TRIF, 1 patient with a mutation in TYK2,1 patients with a mutation in MAVS, and finally 1 patient with a mutation in TBK1)(16) A common polymorphism in TLR3(rs3775291) was linked to increased resistance to HIV1 infection by the genotyping study of Spanish and Italian cohorts with a P value of .023 and .029 respectively. The study compared HIV exposed seronegative cohort(IV drug abuse and sexually active ) with controls. Repetitive HIV exposure in the cohort was evidenced by HCV seropositivity. In vitro infection of PBMCs with HIV showed increased resistance in cells carrying the allele and also TLR3 stimulation by TLR3 agonists showed an increased level of expression of CD69, IL-6, and CCL3(17). A similar study was conducted on the Caucasian population showing the protective effect of the allele against HIV infection(18). Autosomal recessive IRF7 and IRF9 deficiencies impair type I and III IFN immunity and underlie severe influenza pneumonitis. We report three unrelated children with influenza A virus (IAV) infection manifesting as acute respiratory distress syndrome (IAV-ARDS), heterozygous for rare TLR3 variants (P554S in two patients and P680L in the third) causing autosomal dominant (AD) TLR3 deficiency. AD TLR3 deficiency can underlie herpes simplex virus-1 (HSV-1) encephalitis (HSE) by impairing cortical neuron-intrinsic type I IFN immunity to HSV-1. TLR3-mutated leukocytes produce normal levels of IFNs in response to IAV. In contrast, TLR3-mutated fibroblasts produce lower levels of IFN-β and -λ, and display enhanced viral susceptibility, upon IAV infection. Moreover, the patients’ iPSC-derived pulmonary epithelial cells (PECs) are susceptible to IAV. Treatment with IFN-α2b or IFN-λ1 rescues this phenotype. AD TLR3 deficiency may thus underlie IAV-ARDS by impairing TLR3-dependent, type I, and/or III IFN–mediated, PEC-intrinsic immunity. Its clinical penetrance is incomplete for both IAV-ARDS and HSE, consistent with their typically sporadic nature(PMID: 31217193 ) 13.Zhang SY, Jouanguy E, Ugolini S, et al. TLR3 deficiency in patients with herpes simplex encephalitis. Science. 2007;317(5844):1522–1527. doi:10.1126/science.1139522 14.Guo Y, Audry M, Ciancanelli M, et al. Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency: TLR3 is otherwise redundant in protective immunity. J Exp Med. 2011;208(10):2083–2098. doi:10.1084/jem.20101568 15.Lim HK, Seppänen M, Hautala T, et al. TLR3 deficiency in herpes simplex encephalitis: high allelic heterogeneity and recurrence risk. Neurology. 2014;83(21):1888–1897. doi:10.1212/WNL.0000000000000999 16.Mørk N, Kofod-Olsen E, Sørensen KB, et al. Mutations in the TLR3 signaling pathway and beyond in adult patients with herpes simplex encephalitis. Genes Immun. 2015;16(8):552–566. doi:10.1038/gene.2015.46 17.Sironi M, Biasin M, Cagliani R, et al. A common polymorphism in TLR3 confers natural resistance to HIV-1 infection. J Immunol. 2012;188(2):818–823. doi:10.4049/jimmunol.1102179 18.Huik K, Avi R, Pauskar M, et al. Association between TLR3 rs3775291 and resistance to HIV among highly exposed Caucasian intravenous drug users. Infect Genet Evol. 2013;20:78–82. doi:10.1016/j.meegid.2013.08.008 19.Lim HK, Huang SXL, Chen J, et al. Severe influenza pneumonitis in children with inherited TLR3 deficiency. J Exp Med. 2019;216(9):2038–2056. doi:10.1084/jem.20181621 |
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| COVID-19 research v0.137 | ALPI |
Eleanor Williams changed review comment from: Not associated with a phenotype in OMIM or Gene2Phenotype. PMID: 29567797 - Parlato et al 2018- report ALPI mutations in two unrelated patients with severe intestinal inflammation and autoimmunity. WES was used. Patient 1 - non‐consanguineous parents. At 2 years old was diagnosed with coeliac disease from HLA-typing. At age 3 had recurrent abdominal pain, rectal bleeding and severe diarrhoea. Patient 2 - non‐consanguineous parents of Jewish Ashkenazi origin. Age 15 he was diagnosed with ileocolonic Crohn's disease. Compound heterozygous mutations in the ALPI gene were found in both patients. Three variants result in the substitution of residues highly conserved across species (A97T, A350V and A360) and one variant (Q439X) introducing a premature stop codon. Functional studies in HEK293T cells showed that all ALPI mutations were loss of function. ALPI expression was reduced in patients’ biopsies.; to: Not associated with a phenotype in OMIM or Gene2Phenotype. PMID: 29567797 - Parlato et al 2018- report ALPI mutations in two unrelated patients with severe intestinal inflammation and autoimmunity. WES was used. Patient 1 - non‐consanguineous parents. At 2 years old was diagnosed with coeliac disease from HLA-typing. At age 3 had recurrent abdominal pain, rectal bleeding and severe diarrhoea. Patient 2 - non‐consanguineous parents of Jewish Ashkenazi origin. Age 15 he was diagnosed with ileocolonic Crohn's disease. Compound heterozygous mutations in the ALPI gene were found in both patients. Three variants result in the substitution of residues highly conserved across species (A97T, A350V and A360) and one variant (Q439X) introducing a premature stop codon. Functional studies in HEK293T cells showed that all ALPI mutations were loss of function. ALPI expression was reduced in patients’ biopsies. Rated Amber by Zornitza Stark on the PID panel. |
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| COVID-19 research v0.135 | MPO |
Catherine Snow changed review comment from: Comment on list classification: Based on an external review detailing a number of publications where MPO is reviewed because of its association in the regulation of (neutrophil extracellular traps) NET formation upgrading from Amber to Green; to: Comment on list classification: Based on an external review detailing a number of publications where MPO is reviewed because of its association in the regulation of (neutrophil extracellular traps) NET formation upgrading from Amber to Green Should also be noted that elevated levels of inflammatory mediators (including IL-6, IL-8, and MPO) in the airway of chronic/extended or recurrent RSV infection are associated with faster lung function decline in COPD patients. PMID: 32227102 |
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| COVID-19 research v0.135 | MPO | Catherine Snow Publications for gene: MPO were set to 9354683; 15108282; 9637725; 32082301; 27574522; 21703402; 29325098; 29769163; 24968347 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.134 | MPO | Catherine Snow Classified gene: MPO as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.134 | MPO | Catherine Snow Added comment: Comment on list classification: Based on an external review detailing a number of publications where MPO is reviewed because of its association in the regulation of (neutrophil extracellular traps) NET formation upgrading from Amber to Green | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.134 | MPO | Catherine Snow Gene: mpo has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.133 | MPO | Catherine Snow Publications for gene: MPO were set to 9354683; 15108282; 9637725; 32082301; 27574522; 21703402; 29325098; 29769163; 24968347 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.132 | MPO | Catherine Snow Publications for gene: MPO were set to 9354683; 15108282; 9637725; 32082301 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.81 | HLA-DRB1 |
Abdelazeem Elhabyan gene: HLA-DRB1 was added gene: HLA-DRB1 was added to Viral susceptibility. Sources: Literature Mode of inheritance for gene: HLA-DRB1 was set to Unknown Publications for gene: HLA-DRB1 were set to PMID: 19445991,26456283,19597844,10823757, Penetrance for gene: HLA-DRB1 were set to unknown Mode of pathogenicity for gene: HLA-DRB1 was set to Other Review for gene: HLA-DRB1 was set to GREEN Added comment: Association of human leukocyte antigen class II alleles with severe acute respiratory syndrome in the Vietnamese population PMID: 19445991, HLA-DRB1*12 was more frequently shown in SARS patients than in controls (corrected p = 0.042). HLA-DRB1*1202, the predominant allele in the Vietnamese population showed the strongest association with SARS in a dominant model (corrected p = 0.0065 and 0.0052, depending on the controls to be compared). Our results and accumulated data on HLA in the Asian populations would help in the understanding of associations with emerging infectious diseases. Amino Acid Variation in HLA Class II Proteins Is a Major Determinant of Humoral Response to Common Viruses PMID: 26456283 The magnitude of the human antibody response to viral antigens is highly variable. To explore the human genetic contribution to this variability, we performed genome-wide association studies of the immunoglobulin G response to 14 pathogenic viruses in 2,363 immunocompetent adults. Significant associations were observed in the major histocompatibility complex region on chromosome 6 for influenza A virus, Epstein-Barr virus, JC polyomavirus, and Merkel cell polyomavirus. Using local imputation and fine mapping, we identified specific amino acid residues in human leucocyte antigen (HLA) class II proteins as the most probable causal variants underlying these association signals. Common HLA-DRβ1 haplotypes showed virus-specific patterns of humoral-response regulation Clear and Independent Associations of Several HLA-DRB1 Alleles With Differential Antibody Responses to Hepatitis B Vaccination in Youth PMID: 19597844 To confirm and refine associations of human leukocyte antigen (HLA) genotypes with variable antibody (Ab) responses to hepatitis B vaccination, we have analyzed 255 HIV-1 seropositive (HIV(+)) youth and 80 HIV-1 seronegatives (HIV(-)) enrolled into prospective studies. In univariate analyses that focused on HLA-DRB1, -DQA1, and -DQB1 alleles and haplotypes, the DRB1*03 allele group and DRB1*0701 were negatively associated with the responder phenotype (serum Ab concentration > or = 10 mIU/mL) (P = 0.026 and 0.043, respectively). Collectively, DRB1*03 and DRB1*0701 were found in 42 (53.8%) out of 78 non-responders (serum Ab <10 mIU/mL), 65 (40.6%) out of 160 medium responders (serum Ab 10-1,000 mIU/mL), and 27 (27.8%) out of 97 high responders (serum Ab >1,000 mIU/mL) (P < 0.001 for trend). Meanwhile, DRB1*08 was positively associated with the responder phenotype (P = 0.010), mostly due to DRB1*0804 (P = 0.008). Influence of HLA Supertypes on Susceptibility and Resistance to Human Immunodeficiency Virus Type 1 Infection PMID: 10823757 To determine whether HLA polymorphism influences HIV-1 susceptibility, a longitudinal cohort of highly HIV-1-exposed female sex workers based in Nairobi, Kenya, was prospectively analyzed. Decreased HIV-1 infection risk was strongly associated with possession of a cluster of closely related HLA alleles (A2/6802 supertype; incidence rate ratio [IRR], 0.45; 95% confidence interval [CI], 0.27-0.72; P=.0003). The alleles in this supertype are known in some cases to present the same peptide epitopes for T cell recognition. In addition, resistance to HIV-1 infection was independently associated with HLA DRB1*01 (IRR, 0.22; 95% CI, 0.06-0.60; P=.0003), which suggests that anti-HIV-1 class II restricted CD4 effector mechanisms may play an important role in protecting against viral challenge Sources: Literature |
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| COVID-19 research v0.81 | MPO | Abdelazeem Elhabyan reviewed gene: MPO: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 27574522,21703402,29325098,29769163,24968347; Phenotypes: ; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.74 | FPR2 |
Catherine Snow changed review comment from: FPR2 is a seven transmembrane G protein-coupled receptor, which plays an important role in sensing of bacteria and modulation of immune responses Mouse model PMID: 31908042 Fpr2/3 knockout (KO) mice and wild‐type (WT) controls were infected intranasally with S pneumoniae. AnxA1 and Fpr2/3 KO mice were highly susceptible to infection, displaying uncontrolled inflammation, increased bacterial dissemination, and pulmonary dysfunction compared to WT animals PMID: 28928730 The review gives an overview on the pathogenesis of influenza with a focus on the role of FPR2 and discusses the advantages of using FPR2 antagonists to treat the flu. Preclinical studies have proven that FPR2 antagonists efficiently protect mice against IAV infections, by inhibiting viral replication and deleterious inflammation of the lungs; to: FPR2 is a seven transmembrane G protein-coupled receptor, which plays an important role in sensing of bacteria and modulation of immune responses Mouse model PMID: 31908042 Fpr2/3 knockout (KO) mice and wild‐type (WT) controls were infected intranasally with S pneumoniae. AnxA1 and Fpr2/3 KO mice were highly susceptible to infection, displaying uncontrolled inflammation, increased bacterial dissemination, and pulmonary dysfunction compared to WT animals PMID: 28928730 The review gives an overview on the pathogenesis of influenza with a focus on the role of FPR2 and discusses the advantages of using FPR2 antagonists to treat the flu. Preclinical studies have proven that FPR2 antagonists efficiently protect mice against IAV infections, by inhibiting viral replication and deleterious inflammation of the lungs |
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| COVID-19 research v0.74 | FPR2 |
Catherine Snow changed review comment from: FPR2 is a seven transmembrane G protein-coupled receptor, which plays an important role in sensing of bacteria and modulation of immune responses Mouse model PMID: 31908042 Fpr2/3 knockout (KO) mice and wild‐type (WT) controls were infected intranasally with S pneumoniae. AnxA1 and Fpr2/3 KO mice were highly susceptible to infection, displaying uncontrolled inflammation, increased bacterial dissemination, and pulmonary dysfunction compared to WT animals PMID: 28928730 The review gives an overview on the pathogenesis of influenza with a focus on the role of FPR2 and discusses the advantages of using FPR2 antagonists to treat the flu. Preclinical studies have proven that FPR2 antagonists efficiently protect mice against IAV infections, by inhibiting viral replication and deleterious inflammation of the lungs; to: FPR2 is a seven transmembrane G protein-coupled receptor, which plays an important role in sensing of bacteria and modulation of immune responses Mouse model PMID: 31908042 Fpr2/3 knockout (KO) mice and wild‐type (WT) controls were infected intranasally with S pneumoniae. AnxA1 and Fpr2/3 KO mice were highly susceptible to infection, displaying uncontrolled inflammation, increased bacterial dissemination, and pulmonary dysfunction compared to WT animals PMID: 28928730 The review gives an overview on the pathogenesis of influenza with a focus on the role of FPR2 and discusses the advantages of using FPR2 antagonists to treat the flu. Preclinical studies have proven that FPR2 antagonists efficiently protect mice against IAV infections, by inhibiting viral replication and deleterious inflammation of the lungs |
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| COVID-19 research v0.60 | MPO | Sarah Leigh Classified gene: MPO as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.60 | MPO |
Sarah Leigh Added comment: Comment on list classification: PMID 3208230 outlines the role of neutrophil extracellular traps (NETs) in the control of some pathogens including viruses, by virus capture and neutralization. In vivo treatment of the mice with DNase resulted in the enhanced susceptibility of IFNAR-/- mice to the CHIKV virus. Furthermore, the levels of MPO-DNA complex in acutely CHIKV-infected patients, were correlated with the levels of NETs and the viral load in the blood, suggesting that NETs are also released in natural human infection cases. Therefore, variants that result in myeloperoxidase deficiency, may well contribute to an increased susceptiblity to viral infection. At least 9 variants have been reported in Myeloperoxidase deficiency 254600 and these could well be contributing to increased viral susceptibily. |
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| COVID-19 research v0.60 | MPO | Sarah Leigh Gene: mpo has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.44 | MPO | Sarah Leigh Publications for gene: MPO were set to 9354683; 15108282; 9637725 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.40 | C8G |
Ellen McDonagh Source Expert Review Green was added to C8G. Added phenotypes Complement Deficiencies; Complement factor 8 defect; Complement component 8 deficiency; Disseminated neisserial infections for gene: C8G Rating Changed from Red List (low evidence) to Green List (high evidence) |
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| COVID-19 research v0.36 | SERPING1 |
Ellen McDonagh gene: SERPING1 was added gene: SERPING1 was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: SERPING1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: SERPING1 were set to 1597123; 7883978 Phenotypes for gene: SERPING1 were set to Angioedema, hereditary, types I and II 106100; Complement component 4, partial deficiency of 120790; Complement Deficiencies; Hereditary Angioedema (C1inh); Hereditary angioedema |
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| COVID-19 research v0.36 | MPO |
Ellen McDonagh gene: MPO was added gene: MPO was added to Viral susceptibility. Sources: Expert Review Red,ESID Registry 20171117,GRID V2.0 Mode of inheritance for gene: MPO was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MPO were set to 9354683; 15108282; 9637725 Phenotypes for gene: MPO were set to Myeloperoxidase deficiency 254600 |
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| COVID-19 research v0.36 | C8G |
Ellen McDonagh gene: C8G was added gene: C8G was added to Viral susceptibility. Sources: ESID Registry 20171117,Victorian Clinical Genetics Services,GRID V2.0,IUIS Classification December 2019,Expert Review Red,IUIS Classification February 2018 Mode of inheritance for gene: C8G was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C8G were set to 32086639; 32048120 Phenotypes for gene: C8G were set to Complement Deficiencies; Complement factor 8 defect; Complement component 8 deficiency; Disseminated neisserial infections |
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| COVID-19 research v0.36 | C9 |
Ellen McDonagh gene: C9 was added gene: C9 was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: C9 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C9 were set to 9634479; 9570574; 9144525; 10072634 Phenotypes for gene: C9 were set to Mild susceptibility to disseminated neisserial infections; Complement component 9 deficiency; Complement Deficiencies; Susceptibility to invasive bacterial infection, especially meningococcal; C9 deficiency, 613825 |
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| COVID-19 research v0.36 | C8B |
Ellen McDonagh gene: C8B was added gene: C8B was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: C8B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C8B were set to 8098723; 19434484; 9476133; 27183977 Phenotypes for gene: C8B were set to Disseminated neisserial infections; C8 deficiency, type II, 613789; Complement component 8 deficiency; Complement Deficiencies; Susceptibility to invasive bacterial infection, especially meningococcal |
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| COVID-19 research v0.36 | C8A |
Ellen McDonagh gene: C8A was added gene: C8A was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: C8A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C8A were set to 9759902 Phenotypes for gene: C8A were set to Disseminated neisserial infections; Complement component 8 deficiency; C8 deficiency, type I, 613790; Complement Deficiencies; Susceptibility to invasive bacterial infection, especially meningococcal |
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| COVID-19 research v0.36 | C7 |
Ellen McDonagh gene: C7 was added gene: C7 was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: C7 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C7 were set to 16771861; 15554930; 9844043; 7762578 Phenotypes for gene: C7 were set to Disseminated neisserial infections; Complement component 7 deficiency; Complement Deficiencies; C7 deficiency, 610102; Susceptibility to invasive bacterial infection, especially meningococcal |
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| COVID-19 research v0.36 | C6 |
Ellen McDonagh gene: C6 was added gene: C6 was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: C6 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C6 were set to 9472666; 8690922; 12653841 Phenotypes for gene: C6 were set to Disseminated neisserial infections; C6 deficiency, 612446; Complement Deficiencies; Susceptibility to invasive bacterial infection, especially meningococcal; Complement component 6 deficiency |
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| COVID-19 research v0.36 | C5 |
Ellen McDonagh gene: C5 was added gene: C5 was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: C5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C5 were set to 19375167; 25534848; 7730648 Phenotypes for gene: C5 were set to C5 deficiency, 609536; Disseminated neisserial infections; Complement Deficiencies; Complement component 5 deficiency; Susceptibility to invasive bacterial infection, especially meningococcal |
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| COVID-19 research v0.36 | C4A |
Ellen McDonagh gene: C4A was added gene: C4A was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: C4A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C4A were set to 15294999; 2295875; 22482068 Phenotypes for gene: C4A were set to C4a deficiency, 614380; Complement Deficiencies; SLE, infections with encapsulated organisms , partial deficiency is common (either C4A or C4B) and appears to have a modest effect on host defense; Complement component 4 deficiency; SLE predisposition; Immunodeficiency due to a classical component pathway complement deficiency; infections with encapsulated organisms |
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| COVID-19 research v0.36 | C3 |
Ellen McDonagh gene: C3 was added gene: C3 was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: C3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C3 were set to 1350678; 1976733; 15781264; 4117597 Phenotypes for gene: C3 were set to Complement Deficiencies; Complement component 3 deficiency; Atypical hemolytic-uremic syndrome, dense deposit disease; Infections, glomerulonephritis, atypical hemolytic-uremic syndrome with GOF mutations; C3 deficiency, 613779 |
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| COVID-19 research v0.36 | C2 |
Ellen McDonagh gene: C2 was added gene: C2 was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,Inherited complement deficiency v0.11,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: C2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C2 were set to 1577763; 15643297; 11079100; 8621452; 7901282 Phenotypes for gene: C2 were set to Complement Component C2 Deficiency; Lupus; Complement Deficiencies; SLE, infections with encapsulated organisms, atherosclerosis; C2 deficiency, 217000; Immunodeficiency due to C1, C4, or C2 component complement deficiency |
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| COVID-19 research v0.36 | C1S |
Ellen McDonagh gene: C1S was added gene: C1S was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: C1S was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C1S were set to 27745832; 11390518; 20727163; 9856483 Phenotypes for gene: C1S were set to SLE; pyogenic infections; Complement component 1 deficiency; SLE, infections with encapsulated organisms, Ehlers Danlos phenotype; Complement Deficiencies; C1s deficiency, 613783; C1s deficiency, Lupus |
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| COVID-19 research v0.36 | C1R |
Ellen McDonagh gene: C1R was added gene: C1R was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: C1R was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C1R were set to 28544690; 21784777; 27745832; 29795138; 28711143 Phenotypes for gene: C1R were set to SLE; pyogenic infections; Complement component 1 deficiency; SLE, infections with encapsulated organisms, Ehlers Danlos phenotype; Complement Deficiencies; C1r/C1s deficiency, combined, Lupus; Immunodeficiency due to a classical component pathway complement deficiency |
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| COVID-19 research v0.36 | C1QC |
Ellen McDonagh gene: C1QC was added gene: C1QC was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: C1QC was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C1QC were set to 24157463; 8630118; 7900940; 21654842 Phenotypes for gene: C1QC were set to SLE, infections with encapsulated organisms; Complement component 1 deficiency; C1q deficiency, 613652; Complement Deficiencies; Immunodeficiency due to a classical component pathway complement deficiency |
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| COVID-19 research v0.36 | C1QB |
Ellen McDonagh gene: C1QB was added gene: C1QB was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,Inherited complement deficiency v0.11,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: C1QB was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C1QB were set to 9476130; 2894352; 24160257; 12133956; 25454803; 23651859; 17513176 Phenotypes for gene: C1QB were set to SLE, infections with encapsulated organisms; SLE; lupus-like disease; Complement component 1 deficiency; Immunodeficiency due to an early component of complement deficiency, 613652; C1q deficiency; susceptibility to invasive bacterial infection; Complement Deficiencies |
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| COVID-19 research v0.36 | C1QA |
Ellen McDonagh gene: C1QA was added gene: C1QA was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: C1QA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C1QA were set to 7594474; 28601358; 25133636; 8840296; 26032012; 21654842 Phenotypes for gene: C1QA were set to SLE, infections with encapsulated organisms; Complement component 1 deficiency; C1q deficiency, 613652; Complement Deficiencies; Immunodeficiency due to a classical component pathway complement deficiency |
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