| Date | Panel | Item | Activity | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| COVID-19 research v1.133 | ADAR | Arina Puzriakova Phenotypes for gene: ADAR were changed from Fever Syndromes and Related Diseases, Aicardi-Goutieres syndrome 6, 615010; Type 1 interferonopathies; Autoinflammatory Disorders; AGS6; Classical AGS, BSN, SP to Aicardi-Goutieres syndrome 6, OMIM:615010; Fever Syndromes and Related Diseases; Type 1 interferonopathies; Autoinflammatory Disorders | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v1.112 | ADA2 | Arina Puzriakova Phenotypes for gene: ADA2 were changed from Other autoinflammatory diseases with known genetic defect; Evans' syndrome; Polyarteritis nodosa, childhood-onset, 615688; combined immunodeficiency; Polyarteritis nodosa; Deficiency of ADA2 (DADA2); Polyarteritis nodosa, childhood-onset, early-onset recurrent ischemic stroke and fever; Autoinflammatory Disorders; Fever with early onset stroke; ADA2 deficiency to Vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome, OMIM:615688; Polyarteritis nodosa, childhood-onset, early-onset recurrent ischemic stroke and fever; Autoinflammatory Disorders | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v1.17 | CLEC4M |
Sarah Leigh changed review comment from: CLEC4M was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 2 grouping (experimental and/or genetic evidence, suggesting a biological role linking to corona viruses, may not be a GDA); to: CLEC4M was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 2 grouping (experimental and/or genetic evidence, suggesting a biological role linking to corona viruses, may not be a GDA). Illumina review: CLEC4M is a C-type lectin gene serving as cell adhesion receptor and pathogen recognition receptor. It functions as a cellular receptor for variety of viruses, including HIV-1, hepatitis C, Ebola, and SARS-coronavirus. A highly polymorphic variable number tandem repeat (VNTR) at the neck-region of CLEC4M had been associated with genetic predisposition to some infectious diseases, however, genetic association studies have shown conflicting results about these associations (PMID:16991095;16369534;12738250;16364081;17321900;18697825;17534354;17534355). From OMIM: Associated with protection against SARs infection. PMID: 15496474: Jeffers et al. (2004) identified the cellular gylcoprotein CD209L (CLEC4M) as as an alternative receptor for SARS-CoV. CD209L is expressed in human lung in type II alveolar cells and endothelial cells, both potential targets for SARS-CoV. Several other enveloped viruses, including Ebola and Sindbis, also use CD209L as a portal of entry, and HIV and hepatitis C virus can bind to CD209L on cell membranes but do not use it to mediate virus entry. Jeffers et al. (2004) suggested that the large S glycoprotein of SARS-CoV may use both ACE2 and CD209L in virus infection and pathogenesis. PMID 16369534: Chan et al. (2006) - demonstrated that individuals homozygous for CLEC4M tandem repeats are less susceptible to SARS infection. CLEC4M was expressed in both non-SARS and SARS-CoV-infected lung. Compared with cells heterozygous for CLEC4M, cells homozygous for CLEC4M showed higher binding capacity for SARS-CoV, higher proteasome-dependent viral degradation, and a lower capacity for trans infection. Thus, homozygosity for CLEC4M plays a protective role during SARS infection. PMID: 17534354: Tang et al. (2007) - performed genotyping studies in SARS patients and controls and found no support for an association between homozygosity for CLEC4M and protection against SARS. PMID:17534355: Zhi et al. (2007) also failed to replicate the study by Chan et al. (2006). Chan et al. (2007) disputed the validity of both studies. PMID 18697825:Li et al. (2008) - genotyped SNPs in CLEC4M and other genes in the C-type lectin cluster in 181 Chinese SARS patients and 172 controls from an ethnically matched population and found no significant association with disease predisposition or prognosis. However, they detected a population stratification of the CLEC4M variable number tandem repeat (VNTR) alleles in a sample of 1,145 Han Chinese from different parts of China (northeast, south, and southwest). Analysis extended to 742 individuals from 7 ethnic minorities showed that those located along the Silk Road in northwestern China, where there is significant admixture with the European gene pool, had a low level of homozygosity, similar to European populations. Li et al. (2008) concluded that there is no SARS predisposition allele in the lectin gene cluster at chromosome 19p13.3, and that the previously reported association with polymorphisms in the CLEC4M neck region may be due to population stratification. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v1.15 | CD209 |
Sarah Leigh changed review comment from: CD209 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: CD209 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: One SNP associated with susceptibility to HIV infection, severity of dengue disease, increased risk of TB and severity of SARS infection. Pathogen-recognition receptor expressed on the surface of immature dendritic cells (DCs) and involved in initiation of primary immune response. Thought to mediate the endocytosis of pathogens which are subsequently degraded in lysosomal compartments. The receptor returns to the cell membrane surface and the pathogen-derived antigens are presented to resting T-cells via MHC class II proteins to initiate the adaptive immune response. From OMIM:The C-type lectin receptors are involved in the primary interface between host and pathogens. PMID:15564514: Martin et al. (2004) - European Americans at risk for parenteral HIV infection were more likely to carry the -336C SNP in the promoter of DCSIGN. This association was not observed in those at risk for mucosally acquired infection. Although the -336C SNP was common in African Americans, no significant association with risk of infection was observed in this group. PMID:15838506: Sakuntabhai et al. (2005) found that the same CD209 promoter polymorphism reported by Martin et al. (2004) (-336A>G in this study), was associated with severity of dengue disease. Specifically, the G allele of the variant was associated with strong protection against dengue fever as opposed to dengue hemorrhagic fever. PMID:16379498:Barreiro et al. (2006) looked at CD209 polymorphisms in 351 TB patients and 360 healthy controls from a South African Coloured population living in communities with some of the highest reported incidence rates of TB in the world. Identified two variants in the CD209 promoter, -871A and -336G, that were associated with increased risk of TB. PMID:20864747: Chan et al. (2010) - A single nucleotide polymorphism in the promoter region of the DC-SIGN gene is associated with disease severity in SARS. In the DC_SIGN promoter region, a single SNP, -336A>G has been found to affect transcription of DC-SIGN in vitro and is associated with susceptibility for HIV-1 and M. tuberculosis infectsions and with the severity of dengue (PMID:15838506;15838506;16379498). Large case-control study - genotyped the SNP in 824 SARS patients and 471 controls. Showed no association with susceptibility to infection but SARS patients carrying the DC-SIGN promoter -336G variant had lower risk of having higher lactate dehydrogenase levels on admission, an independent prognostic indicator for severity of SARS-CoV infection. In vitro functional studies demonstrated that the DC-SIGN -336G promoter provided a less effective binding site and lower promoter activity, which may lead to reduced DC-SIGN protein expression and hence may contribute to a reduced immune-response with reduced lung injury during the progression of SARS infection. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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). |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.349 | BECN1 |
Rebecca Foulger commented on gene: BECN1: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): BECN1 encodes the beclin1 protein which is an established regulator of the autophagic pathway. Autophagy is a key mechanism against invading bacteria, parasites, and viruses in innate immune cells including monocytes/macrophages, dendritic cells and neutrophils (reviewed in Tao et al. 2020). Viral proteins such as HIV-1 Nef, ICP34.5 of HSV-1 and M11 of MHV-68 have been shown to interact with Beclin-1 and block the late stage of autophagy, thereby protecting viral particles from degradation (Kyei et al 2009; Orvedahl et al. (2007); Ku et al. (2008) PMID:32265919 Tao et al. 2020 (review) - Autophagy is a key mechanism against invading bacteria, parasites, and viruses in innate immune cells including monocytes/macrophages, dendritic cells (conventional dendritic cells-cDCs and plasmacytoid dendritic cells-pDCs) and neutrophils. BECN1 encodes beclin1 protein which is an established regulator of the autophagic pathway. Viral proteins may target BECN1 to inhibit autophagy. PMID: 19635843 Kyei et al. (2009) - A series of experiments showed that the Nef protein of HIV inhibits the autophagic maturation pathway (fig 5). Macrophages transfected with Nef-GFP showed colocalization of Nef with Beclin-1 and the two proteins were shown to physically interact in immunoprecipitation experiments (Fig6). PMID: 18248095 Ku et al. (2008) - In NIH3T3 cell culture studies, the M11, a viral BCL-2 of murine gamma herpesvirus 68 was shown to bind Beclin-1 and to inhibit to inhibit Beclin-1 mediated autophagy (Fig 4). PMID: 18005679 Orvedahl et al. (2007) - The authors used coimmunoprecipitation experiments in both HEK293 cells and embryonic stem cells to show that the neurovirulence protein of Herpes simplex virus (HSV)-1, ICP34.5, binds to the C terminus of BECN1 (Fig 2). In MCF7 stably expressing BECN1cells, transfection of the ICP34.5 inhibited autophagy (Fig 2). Mutant HSV-1 lacking the ICP34.5 BECN1-binding domain failed to inhibit autophagy in primary sympathetic neurons (Fig 5A) and had impaired ability to cause lethal encephalitis in mice (Fig 6) . |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 | IDE | Alison Coffey commented on gene: IDE: Evidence Summary from Illumina curation team: Insulin-degrading enzyme (IDE), also known as insulysin, is a member of the zinc metalloproteinase family that was initially implicated in insulin degradation. It is highly conserved among different species and has the ability to interact with a variety of functionally unrelated ligands that share little homology in their primary amino acid sequences. Several human viruses use enzymes as receptors. Li et al. (2006) (PMID 17055432) established IDE as a cellular receptor for both cell-free and cell-associated Varicella-zoster virus (VZV), the cause of chickenpox and shingles in humans. VZV is likely spread as cell-free virus to susceptible hosts but transmitted by cell-to-cell spread in the body and in vitro. Li et al. (2006) showed that IDE interacts with the VZV glycoprotein E (gE) (which is essential for virus infection) through its extracellular domain. Downregulation of IDE by siRNA, or blocking of IDE with antibody, with soluble IDE protein extracted from liver, or with bacitracin inhibited VZV infection. Cell-to-cell spread of virus was also impaired by blocking IDE. Transfection of cell lines impaired for VZV infection with a plasmid expressing human IDE resulted in increased entry and enhanced infection with cell-free and cell-associated virus. Li et al. (2010) subsequently reported that a recombinant soluble IDE (rIDE) enhanced VZV infectivity at an early step of infection associated with an increase in virus internalization, and increased cell-to-cell spread. In 2017, Hahn et al. demonstrated that mature HIV-1 p6 protein (stability of which inversely affects the replication capacity of HIV-1) is a substrate for IDE. IDE is both sufficient and required for the degradation of p6, which is approximately 100-fold more efficiently degraded by IDE than its eponymous substrate insulin. An IDE specific inhibitor, 6bK, and exogenous insulin, were both shown to interfere with X4-tropic HIV-1 replication in activated PBMCs, most probably by competing with p6 for degradation by IDE. In addition, an IDE-insensitive p6 mutant of HIV-1 exhibits impaired replication capacity but is insensitive to treatment with insulin or 6bK. Conversely, neither virus release and maturation, nor the amounts of particle associated Vpr and p6 itself were altered in IDE knock out cells. The data support a model in which IDE is responsible for the rapid degradation of p6 entering the cell as part of the incoming virion, a process that appears to be crucial to achieve optimal X4-tropic virus replication. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 | TLR7 | Alison Coffey commented on gene: TLR7: Evidence Summary from Illumina curation team: The TLR7 gene encodes for toll -like receptor 7 protein, an endosomal receptor that plays a key role in innate and adaptive immunity. Toll-like receptors are pattern recognition receptors, which control host immune response against pathogens through recognition of molecular signatures. TLR7 recognizes uridine-containing single strand RNAs (ssRNAs) of viral origin or guanosine analog (reviewed by Freund et al. 2019). Tlr7 deficient mice show an increased susceptibility to West Nile Virus (Town et al. (2009) and recently, Mukherjee et al. (2019) identified TLR7 polymorphisms associated with susceptibility to viral infections in an East Asian population Mukherjee et al. (2019). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.347 | IFNA1 | Alison Coffey commented on gene: IFNA1: Evidence Summary from Illumina curation team: IFNA1 encodes IFN alpha, and belongs to the family of type I IFNs which bind to and activate the IFNAR receptor complex. Type I Interferons (IFN-I) mediate numerous immune interactions during viral infections, they establish an antiviral state as well as invoke and regulate innate and adaptive immune cells that eliminate infection (Lukele et al. 2019, review; Wang et al.2019 review). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.150 | ADAM17 | Rebecca Foulger Publications for gene: ADAM17 were set to 22010916; 20603312; 25058236; 32086639; 11149563; 28930861; 32048120; 25171914 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.137 | ADAM17 | Eleanor Williams reviewed gene: ADAM17: Rating: ; Mode of pathogenicity: None; Publications: 22010916, 26683521, 25804906, 29560122; Phenotypes: ?Inflammatory skin and bowel disease, neonatal, 1 #614328; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.109 | PARP1 |
Sarah Leigh changed review comment from: PARP1 Enhances Influenza A Virus Propagation by Facilitating Degradation of Host Type I Interferon Receptor. Therefore, activiation of PARP1 could promote Influenza infection. Sources: Literature; to: PARP1 Enhances Influenza A Virus Propagation by Facilitating Degradation of Host Type I Interferon Receptor. Therefore, activiation of PARP1 could promote Influenza infection, by interfering with the IFNAR1. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.109 | PARP1 |
Sarah Leigh gene: PARP1 was added gene: PARP1 was added to Viral susceptibility. Sources: Literature Mode of inheritance for gene: PARP1 was set to Unknown Publications for gene: PARP1 were set to 31915279 Added comment: PARP1 Enhances Influenza A Virus Propagation by Facilitating Degradation of Host Type I Interferon Receptor. Therefore, activiation of PARP1 could promote Influenza infection. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.61 | ADAM17 | Abdelazeem Elhabyan reviewed gene: ADAM17: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.61 | ADAM17 | Abdelazeem Elhabyan reviewed gene: ADAM17: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.51 | IFNAR1 |
Sarah Leigh Added comment: Comment on publications: PMID 31270247: reports three variants in two cases of healthy children with adverse reactions to live attuated virus vaccines. Each had biallelic loss-of-function IFNAR1 variations and the effects of these was demonstrated by the patient-derived fibroblasts being susceptible to viruses. This effect was recused by the WT IFNAR1. PMID 26676772: reports the tageted degradation of IFNAR1 protein by Influenza A virus (IAV), allowing the virus to escape the powerful innate immune system. Thus the loss of function of IFNAR1 would increase the susceptability to viral infection. PMID 20020050: reports the tageted degradation of IFNAR1 protein by Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV). Confocal microscopic analysis showed increased translocation of IFNAR1 into the lysosomal compartment and flow cytometry showed reduced levels of IFNAR1 in 3a-expressing cells. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.40 | SAMD9 |
Ellen McDonagh Source Expert Review Green was added to SAMD9. Added phenotypes IUGR with gonadal abnormalities, adrenal failure, MDS with chromosome 7 aberrations, predisposition to infections, enteropathy, absent spleen; MIRAGE syndrome (Myelodysplasia, Infection, Restriction of growth, Adrenal insufficiency, Genital phenotypes, and Enteropathy); ataxia-thrombocytopenia syndrome; Bone marrow failure; Combined immunodeficiencies with associated or syndromic features for gene: SAMD9 Rating Changed from Amber List (moderate evidence) to Green List (high evidence) |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.40 | ADAM17 |
Ellen McDonagh Source Expert Review Green was added to ADAM17. Added phenotypes IBD-1; ADAM17 deficiency; Inflammatory skin and bowel disease, neonatal, 1; Inflammatory skin and bowel disease, neonatal 1, 614328; Autoinflammatory Disorders; inflammatory skin; Early onset diarrhea and skin lesions for gene: ADAM17 Rating Changed from Amber List (moderate evidence) to Green List (high evidence) |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.36 | SAMD9 |
Ellen McDonagh gene: SAMD9 was added gene: SAMD9 was added to Viral susceptibility. Sources: IUIS Classification December 2019,IUIS Classification February 2018,Expert Review Amber Mode of inheritance for gene: SAMD9 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: SAMD9 were set to 29175836; 32086639; 29266745; 29535429; 28487541; 32048120 Phenotypes for gene: SAMD9 were set to IUGR with gonadal abnormalities, adrenal failure, MDS with chromosome 7 aberrations, predisposition to infections, enteropathy, absent spleen; MIRAGE syndrome (Myelodysplasia, Infection, Restriction of growth, Adrenal insufficiency, Genital phenotypes, and Enteropathy); ataxia-thrombocytopenia syndrome; Bone marrow failure; Combined immunodeficiencies with associated or syndromic features |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.36 | AIRE |
Ellen McDonagh gene: AIRE was added gene: AIRE was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,GOSH PID v.8.0,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: AIRE was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Publications for gene: AIRE were set to 9888391; 19807739; 11600535; 11836330; 10677297; 29437776; 29108822; 19758376; 9398839; 9837820; 28911151 Phenotypes for gene: AIRE were set to Autoimmune polyendocrinopathy syndrome, type I, with or without reversible metaphyseal dysplasia, 240300; Multiple endocrine deficiency Addison disease candidiasis syndrome; Autoimmune hypoparathyroidism chronic candidiasis Addison disease syndrome; Diseases of Immune Dysregulation; Chronic mucocutaneous candidiasis (CMC); Autoimmunity: hypoparathyroidism hypothyroidism, adrenal insufficiency, diabetes, gonadal dysfunction and other endocrine abnormalities, chronic mucocutaneous candidiasis, dental enamel hypoplasia, alopecia areata enteropathy, pernicious anemia; Hypoparathyroidism Addison disease mucocutaneous candidiasis syndrome; Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.36 | ADAM17 |
Ellen McDonagh gene: ADAM17 was added gene: ADAM17 was added to Viral susceptibility. Sources: Victorian Clinical Genetics Services,North West GLH,GRID V2.0,NHS GMS,GOSH PID v.8.0,London North GLH,IUIS Classification December 2019,IUIS Classification February 2018,Expert Review Amber Mode of inheritance for gene: ADAM17 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ADAM17 were set to 22010916; 20603312; 25058236; 32086639; 11149563; 28930861; 32048120; 25171914 Phenotypes for gene: ADAM17 were set to IBD-1; ADAM17 deficiency; Inflammatory skin and bowel disease, neonatal, 1; Inflammatory skin and bowel disease, neonatal 1, 614328; Autoinflammatory Disorders; inflammatory skin; Early onset diarrhea and skin lesions |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.36 | ADAR |
Ellen McDonagh gene: ADAR was added gene: ADAR 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: ADAR was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ADAR were set to 25604658; 24183309; 23001123; 24262145; 27643693; 25769924 Phenotypes for gene: ADAR were set to Fever Syndromes and Related Diseases, Aicardi-Goutieres syndrome 6, 615010; Type 1 interferonopathies; Autoinflammatory Disorders; AGS6; Classical AGS, BSN, SP |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.36 | ADA2 |
Ellen McDonagh gene: ADA2 was added gene: ADA2 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: ADA2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ADA2 were set to 24552284; 26922074; 24552285; 29564582 Phenotypes for gene: ADA2 were set to Other autoinflammatory diseases with known genetic defect; Evans' syndrome; Polyarteritis nodosa, childhood-onset, 615688; combined immunodeficiency; Polyarteritis nodosa; Deficiency of ADA2 (DADA2); Polyarteritis nodosa, childhood-onset, early-onset recurrent ischemic stroke and fever; Autoinflammatory Disorders; Fever with early onset stroke; ADA2 deficiency |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.36 | ADA |
Ellen McDonagh gene: ADA was added gene: ADA was added to Viral susceptibility. Sources: Expert Review Green,Combined B and T cell defect v1.12,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,GOSH PID v.8.0,London North GLH,SCID v1.6,IUIS Classification February 2018 Mode of inheritance for gene: ADA was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ADA were set to Severe combined immunodeficiency due to ADA deficiency, 102700; Low NK, bone defects, may have pulmonary alveolar proteinosis, cognitive defects; Atypical Severe Combined Immunodeficiency (Atypical SCID); Immunodeficiencies affecting cellular and humoral immunity; Adenosine deaminase (ADA) deficiency; T-B+ SCID; Omenn syndrome; Severe combined immunodeficiency (SCID); T-B- SCID; Severe combined immunodeficiency due to ADA deficiency (some mosiacism noted) |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||