tetano
Editor, Senior Moderator
J Virol. 2015 Jan 14. pii: JVI.03610-14. [Epub ahead of print]
[h=1]A host susceptibility gene, DR1, Facilitates Influenza A Virus Replication via Suppressing Host Innate Immunity and Enhancing Viral RNA Replication.[/h] Hsu SF[SUP]1[/SUP], Su WC[SUP]2[/SUP], Jeng KS[SUP]3[/SUP], Lai MM[SUP]4[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Influenza A virus (IAV) depends on cellular factors to complete its replication cycle; thus, investigation of the factors utilized by IAV could facilitate antiviral drug development. To this end, a cellular transcriptional repressor, DR1, was identified from a genome-wide RNAi screen. Knockdown (KD) of DR1 resulted in reduction of the viral RNA and protein production, demonstrating that DR1 acts as a positive host factor in IAV replication. Genome-wide transcriptomic analysis showed that there was strong induction of interferon-stimulated genes (ISGs) expression after prolonged DR1 KD. We found that IFNβ was induced by DR1 KD, thereby activating the JAK-STAT pathway to turn on ISGs expression, which led to strong inhibition of IAV replication. This result suggests that DR1 in normal cells suppresses IFN induction probably to prevent undesired cytokine production, but this suppression could create a milieu that favors IAV replication once cells are infected. Furthermore, biochemical assays of the viral RNA replication showed that DR1 KD suppressed the viral RNA replication. We also showed that DR1 associated with all three subunits of the viral RNA-dependent RNA polymerase (RdRp) complex, indicating that DR1 may be through interacting with individual components of the viral RdRp complex to enhance the viral RNA replication. Thus, DR1 could be considered a novel host susceptibility gene for IAV replication via dual mechanisms, which not only suppresses host defense to indirectly favor IAV replication but also directly facilitates the viral RNA replication.
[h=4]IMPORTANCE:[/h] Investigation of virus-host interactions involved in influenza A virus replication is important for understanding the viral pathogenesis and the host defenses, which could manipulate influenza virus infection or prevent the emergence of drug resistance caused by high error rate during the viral RNA replication. For this purpose, a cellular transcriptional repressor, DR1, was identified from a genome-wide RNAi screen as a positive regulator in IAV replication. In the current studies, we showed that DR1 suppresses the gene expression of a large set of host innate immunity, which indirectly facilitates IAV replication in the event of IAV infection. Besides this scenario, DR1 also directly enhanced the viral RdRp activity likely through associating with individual components of the viral RdRp complex. Thus, DR1 represents a novel host susceptibility gene for IAV replication via multiple functions, which not only suppresses host defense but also enhances the viral RNA replication. DR1 may be a potential target for drug development against influenza infection.
Copyright ? 2015, American Society for Microbiology. All Rights Reserved.
PMID: 25589657 [PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/25589657
[h=1]A host susceptibility gene, DR1, Facilitates Influenza A Virus Replication via Suppressing Host Innate Immunity and Enhancing Viral RNA Replication.[/h] Hsu SF[SUP]1[/SUP], Su WC[SUP]2[/SUP], Jeng KS[SUP]3[/SUP], Lai MM[SUP]4[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Influenza A virus (IAV) depends on cellular factors to complete its replication cycle; thus, investigation of the factors utilized by IAV could facilitate antiviral drug development. To this end, a cellular transcriptional repressor, DR1, was identified from a genome-wide RNAi screen. Knockdown (KD) of DR1 resulted in reduction of the viral RNA and protein production, demonstrating that DR1 acts as a positive host factor in IAV replication. Genome-wide transcriptomic analysis showed that there was strong induction of interferon-stimulated genes (ISGs) expression after prolonged DR1 KD. We found that IFNβ was induced by DR1 KD, thereby activating the JAK-STAT pathway to turn on ISGs expression, which led to strong inhibition of IAV replication. This result suggests that DR1 in normal cells suppresses IFN induction probably to prevent undesired cytokine production, but this suppression could create a milieu that favors IAV replication once cells are infected. Furthermore, biochemical assays of the viral RNA replication showed that DR1 KD suppressed the viral RNA replication. We also showed that DR1 associated with all three subunits of the viral RNA-dependent RNA polymerase (RdRp) complex, indicating that DR1 may be through interacting with individual components of the viral RdRp complex to enhance the viral RNA replication. Thus, DR1 could be considered a novel host susceptibility gene for IAV replication via dual mechanisms, which not only suppresses host defense to indirectly favor IAV replication but also directly facilitates the viral RNA replication.
[h=4]IMPORTANCE:[/h] Investigation of virus-host interactions involved in influenza A virus replication is important for understanding the viral pathogenesis and the host defenses, which could manipulate influenza virus infection or prevent the emergence of drug resistance caused by high error rate during the viral RNA replication. For this purpose, a cellular transcriptional repressor, DR1, was identified from a genome-wide RNAi screen as a positive regulator in IAV replication. In the current studies, we showed that DR1 suppresses the gene expression of a large set of host innate immunity, which indirectly facilitates IAV replication in the event of IAV infection. Besides this scenario, DR1 also directly enhanced the viral RdRp activity likely through associating with individual components of the viral RdRp complex. Thus, DR1 represents a novel host susceptibility gene for IAV replication via multiple functions, which not only suppresses host defense but also enhances the viral RNA replication. DR1 may be a potential target for drug development against influenza infection.
Copyright ? 2015, American Society for Microbiology. All Rights Reserved.
PMID: 25589657 [PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/25589657