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

¹ University of California at Davis;
² University of Maryland at College Park

³ E-mail: zxing{at}ucdavis.edu

The NS1 protein is known to suppress immune responses in influenza virus-infected hosts. However, the role of NS1 in apoptosis in infected cells has been controversial. 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 (IFNs) in chicken macrophages. However, NS1 appeared to be irrelevant to the regulation of cytokines 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 Fas/Fas ligand (FasL)-mediated pathway. We found that NS1 suppressed the apoptotic process through suppression of the induction of the FasL, but not TNF-b or TRAIL. Further, our data indicated that the disruption of a potential binding site for the p85b subunit of phosphoinositide 3-kinase (PI3K) 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. Suppression of Fas/FasL-mediated apoptosis by NS1, therefore, is one of the critical mechanisms to increase infectivity in AIV-infected chicken macrophages.

Received 24 September 2008; accepted 9 January 2009.