Differential regulation of antiviral and proinflammatory cytokines and suppression of Fas-mediated apoptosis by NS1 of H9N2 avian influenza virus in chicken macrophages

• Published in: Journal of general virology 2009-05, Vol.90 (5), p.1109-1118
• Main Authors: Xing, Zheng, Cardona, Carol J, Adams, Sean, Yang, Zengqi, Li, Jinling, Perez, Daniel, Woolcock, Peter R
• Format: Article
• Language: English
• Subjects: Animals; apoptosis; Apoptosis - physiology; Avian influenza virus; Biological and medical sciences; Chickens; cytokines; Cytokines - genetics; Cytokines - metabolism; Fas Ligand Protein - metabolism; fas Receptor - genetics; fas Receptor - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Viral - physiology; immune response; infection; Influenza A virus; Influenza A Virus, H9N2 Subtype; Influenza in Birds - virology; interferons; interleukin-1; interleukin-6; macrophages; Macrophages - metabolism; Macrophages - virology; Microbiology; NS1 protein; Phasianidae; phosphoinositide 3-kinase; Replicative cycle, interference, host-virus relations, pathogenicity, miscellaneous strains; Viral Nonstructural Proteins - metabolism; viral proteins; Virology
• ISSN: 0022-1317; 1465-2099
• DOI: 10.1099/vir.0.007518-0

The NS1 protein is known to suppress immune responses in influenza virus-infected hosts. However, the role of NS1 in apoptosis in infected cells is disputed. In this study, through the use of a mutant A/pheasant/California/2373/1998 (H9N2) avian influenza virus (AIV) with a truncated NS1, we have demonstrated that a functional NS1 protein suppresses the induction of interferons in chicken macrophages. However, NS1 appeared to be irrelevant to the regulation of cytokines interleukin (IL)-1β and IL-6, indicating that distinct mechanisms may be employed in the regulation of antiviral and proinflammatory cytokines in chicken immune cells. Our study also showed that this H9N2 AIV induced apoptosis extrinsically through the Fas/Fas ligand (FasL)-mediated pathway. We found that NS1 suppressed the apoptotic process through suppression of the induction of FasL, but not tumour necrosis factor-α or TNF-related apoptosis-inducing ligand. Furthermore, our data indicated that the disruption of a potential binding site for the p85β subunit of phosphoinositide 3-kinase in the carboxyl terminus of NS1, while having no effect on the regulation of IFN induction, may contribute to the suppression of Fas/FasL-mediated apoptosis. Therefore, suppression of Fas/FasL-mediated apoptosis by NS1 is one of the critical mechanisms necessary to increase infectivity in AIV-infected chicken macrophages.