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COVID-19 research v0.347 ATF3 Rebecca Foulger changed review comment from: Evidence Summary from Illumina curation team: The Activating Transcription Factor 3 (ATF3) is a member of the ATF/cAMP Responsive Element-Binding (CREB) family of transcription factors which are known to be induced during inflammation and genotoxic stress. The modulation and elevation of ATF3 levels has also been observed in different host cells types upon infection with viruses, including the coronavirus, HCoV-229E and the Japanese encephalitis virus (JEV), a RNA neurotropic flavivirus (Poppe et al. 2016; Sood et al. (2017). In a mouse neuronal cell line infected with JEV, Atf3 was shown to bind to the promoter of viral response genes including Stat1, Irf9, Isg15, and to negatively regulate their expression (Sood et al. (2017). In addition, cellular autophagy was also inhibited by Atf3 negative regulation of the autophagy gene Atg5 in cells infected with the same virus (Sood et al. (2017). Labzin et al. (2015) also showed reduced viral replication in primary bone marrow–derived macrophages derived from Atf3 deficient mice, a phenotype which could be rescued by overexpression of Atf3.
PMID: 28355270: Poppe et al. (2016) -The A549 lung epithelial carcinoma cell model was used to assess host cell transcriptional changes upon infection of the corona virus HCoV-229E. At 16 h and 48 h post transfection, cell transcriptomes were analysed by microarray containing 60,000 probes covering annotated genes and non-coding RNAs. Thirty seven genes, including ATF3 were upregulated in response to the HCoV-229E infection when compared to mock transduced cells (Fig 1). Upregulation of ATF3 was confirmed by RT-PCR analysis of laser dissected cells (Fig 1E).
PMID 28821775; Sood et al. (2017) - ATF3 is induced following Japanese encephalitis virus (JEV) infection, and regulates cellular antiviral and autophagy pathways in the absence of type I interferons in mouse neuronal cells. ATF3 was induced in mammalian cells following JEV infection, using qRTPCR analysis of transduced cell lines, including mouse Neuro2a, HEK293, HeLa and MEFs ATF3 levels were elevated compared to wildtype (Fig1). Fig2: ATF3 acts as a negative regulator of the antiviral response. Knockdown of ATF3 expression using Atf3 specific siRNA lead to a relative increased expression of viral response genes including Rig1, ifih1, ddx60, Gbp1, compared to controls. Fig4 CHIP analysis showed that ATF3 binds to the promoter of antiviral genes such as Stat1, Irf9, Isg15, Ifit1. Fig5 ATF3 negatively regulates cellular autophagy, in both Neur2a cells and MEFs infected with JEV and treated with Atf3 siRNA showed a relative increase in the expression of cellular autophagy related genes as determined by RTPCR. Fig 6. CHIP analysis showed that ATF3 binds the ATG5 promoter. Taken together this series of experiments demonstrate that, in cells deficient in interferon type I, the increased expression of ATF3 induced by infection of JEV leads to the negative regulation of antiviral genes such as Stat1, Irf9, Isg15 and genes related to cellular autophagy such as ATG5.
PMID 26416280; Labzin et al. (2015) - ATF3 limits cellular inflammatory response to microbial infection by regulating the expression of cytokines and chemokines. Primary bone marrow–derived macrophages from ATF3-/- mice infected with LCMV showed reduced viral replication compared to WT (Fig 7). The same cells overexpressing ATF3 constructs showed an increase in viral replication.; to: Evidence Summary from Illumina curation team: The Activating Transcription Factor 3 (ATF3) is a member of the ATF/cAMP Responsive Element-Binding (CREB) family of transcription factors which are known to be induced during inflammation and genotoxic stress. The modulation and elevation of ATF3 levels has also been observed in different host cells types upon infection with viruses, including the coronavirus, HCoV-229E and the Japanese encephalitis virus (JEV), a RNA neurotropic flavivirus (Poppe et al. 2016; Sood et al. (2017). In a mouse neuronal cell line infected with JEV, Atf3 was shown to bind to the promoter of viral response genes including Stat1, Irf9, Isg15, and to negatively regulate their expression (Sood et al. (2017). In addition, cellular autophagy was also inhibited by Atf3 negative regulation of the autophagy gene Atg5 in cells infected with the same virus (Sood et al. (2017). Labzin et al. (2015) also showed reduced viral replication in primary bone marrow–derived macrophages derived from Atf3 deficient mice, a phenotype which could be rescued by overexpression of Atf3.

PMID: 28355270: Poppe et al. (2016) -The A549 lung epithelial carcinoma cell model was used to assess host cell transcriptional changes upon infection of the corona virus HCoV-229E. At 16 h and 48 h post transfection, cell transcriptomes were analysed by microarray containing 60,000 probes covering annotated genes and non-coding RNAs. Thirty seven genes, including ATF3 were upregulated in response to the HCoV-229E infection when compared to mock transduced cells (Fig 1). Upregulation of ATF3 was confirmed by RT-PCR analysis of laser dissected cells (Fig 1E).

PMID 28821775; Sood et al. (2017) - ATF3 is induced following Japanese encephalitis virus (JEV) infection, and regulates cellular antiviral and autophagy pathways in the absence of type I interferons in mouse neuronal cells. ATF3 was induced in mammalian cells following JEV infection, using qRTPCR analysis of transduced cell lines, including mouse Neuro2a, HEK293, HeLa and MEFs ATF3 levels were elevated compared to wildtype (Fig1). Fig2: ATF3 acts as a negative regulator of the antiviral response. Knockdown of ATF3 expression using Atf3 specific siRNA lead to a relative increased expression of viral response genes including Rig1, ifih1, ddx60, Gbp1, compared to controls. Fig4 CHIP analysis showed that ATF3 binds to the promoter of antiviral genes such as Stat1, Irf9, Isg15, Ifit1. Fig5 ATF3 negatively regulates cellular autophagy, in both Neur2a cells and MEFs infected with JEV and treated with Atf3 siRNA showed a relative increase in the expression of cellular autophagy related genes as determined by RTPCR. Fig 6. CHIP analysis showed that ATF3 binds the ATG5 promoter. Taken together this series of experiments demonstrate that, in cells deficient in interferon type I, the increased expression of ATF3 induced by infection of JEV leads to the negative regulation of antiviral genes such as Stat1, Irf9, Isg15 and genes related to cellular autophagy such as ATG5.

PMID 26416280; Labzin et al. (2015) - ATF3 limits cellular inflammatory response to microbial infection by regulating the expression of cytokines and chemokines. Primary bone marrow–derived macrophages from ATF3-/- mice infected with LCMV showed reduced viral replication compared to WT (Fig 7). The same cells overexpressing ATF3 constructs showed an increase in viral replication.
COVID-19 research v0.347 ATF3 Rebecca Foulger commented on gene: ATF3: Evidence Summary from Illumina curation team: The Activating Transcription Factor 3 (ATF3) is a member of the ATF/cAMP Responsive Element-Binding (CREB) family of transcription factors which are known to be induced during inflammation and genotoxic stress. The modulation and elevation of ATF3 levels has also been observed in different host cells types upon infection with viruses, including the coronavirus, HCoV-229E and the Japanese encephalitis virus (JEV), a RNA neurotropic flavivirus (Poppe et al. 2016; Sood et al. (2017). In a mouse neuronal cell line infected with JEV, Atf3 was shown to bind to the promoter of viral response genes including Stat1, Irf9, Isg15, and to negatively regulate their expression (Sood et al. (2017). In addition, cellular autophagy was also inhibited by Atf3 negative regulation of the autophagy gene Atg5 in cells infected with the same virus (Sood et al. (2017). Labzin et al. (2015) also showed reduced viral replication in primary bone marrow–derived macrophages derived from Atf3 deficient mice, a phenotype which could be rescued by overexpression of Atf3.
PMID: 28355270: Poppe et al. (2016) -The A549 lung epithelial carcinoma cell model was used to assess host cell transcriptional changes upon infection of the corona virus HCoV-229E. At 16 h and 48 h post transfection, cell transcriptomes were analysed by microarray containing 60,000 probes covering annotated genes and non-coding RNAs. Thirty seven genes, including ATF3 were upregulated in response to the HCoV-229E infection when compared to mock transduced cells (Fig 1). Upregulation of ATF3 was confirmed by RT-PCR analysis of laser dissected cells (Fig 1E).
PMID 28821775; Sood et al. (2017) - ATF3 is induced following Japanese encephalitis virus (JEV) infection, and regulates cellular antiviral and autophagy pathways in the absence of type I interferons in mouse neuronal cells. ATF3 was induced in mammalian cells following JEV infection, using qRTPCR analysis of transduced cell lines, including mouse Neuro2a, HEK293, HeLa and MEFs ATF3 levels were elevated compared to wildtype (Fig1). Fig2: ATF3 acts as a negative regulator of the antiviral response. Knockdown of ATF3 expression using Atf3 specific siRNA lead to a relative increased expression of viral response genes including Rig1, ifih1, ddx60, Gbp1, compared to controls. Fig4 CHIP analysis showed that ATF3 binds to the promoter of antiviral genes such as Stat1, Irf9, Isg15, Ifit1. Fig5 ATF3 negatively regulates cellular autophagy, in both Neur2a cells and MEFs infected with JEV and treated with Atf3 siRNA showed a relative increase in the expression of cellular autophagy related genes as determined by RTPCR. Fig 6. CHIP analysis showed that ATF3 binds the ATG5 promoter. Taken together this series of experiments demonstrate that, in cells deficient in interferon type I, the increased expression of ATF3 induced by infection of JEV leads to the negative regulation of antiviral genes such as Stat1, Irf9, Isg15 and genes related to cellular autophagy such as ATG5.
PMID 26416280; Labzin et al. (2015) - ATF3 limits cellular inflammatory response to microbial infection by regulating the expression of cytokines and chemokines. Primary bone marrow–derived macrophages from ATF3-/- mice infected with LCMV showed reduced viral replication compared to WT (Fig 7). The same cells overexpressing ATF3 constructs showed an increase in viral replication.
COVID-19 research v0.36 IFIH1 Ellen McDonagh Mode of inheritance for gene IFIH1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mode of pathogenicity for gene IFIH1 was changed from None to Other - please provide details in the comments
Added phenotypes Rhinovirus and other RNA viruses (AR); Classical AGS, SLE, SP, SMS; Autoinflammatory Disorders; Defects in Intrinsic and Innate Immunity; Aicardi-Goutieres syndrome 7 (AD); susceptibility to RNA viruses for gene: IFIH1
Publications for gene IFIH1 were updated from 29018476; 28606988 to 29018476; 28606988; 28716935
COVID-19 research v0.32 IFIH1 Ellen McDonagh Publications for gene: IFIH1 were set to 29018476
COVID-19 research v0.31 IFIH1 Ellen McDonagh Classified gene: IFIH1 as Green List (high evidence)
COVID-19 research v0.31 IFIH1 Ellen McDonagh Added comment: Comment on list classification: Biallelic variants associated with susceptibility to RNA viruses.
COVID-19 research v0.31 IFIH1 Ellen McDonagh Gene: ifih1 has been classified as Green List (High Evidence).
COVID-19 research IFIH1 Ellen McDonagh classified IFIH1 as Red List (low evidence)
COVID-19 research IFIH1 Ellie McDonagh edited their review of IFIH1