Differential regulation of antiviral and proinflammatory cytokines and suppression of Fas-mediated apoptosis by NS1 of H9N2 avian influenza virus in chicken macrophages.
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)-1beta 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-alpha or TNF-related apoptosis-inducing ligand. Furthermore, our data indicated that the disruption of a potential binding site for the p85beta 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.
Xing
Zheng
Z
Veterinary Medicine Extension, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.|Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.
Cardona
Carol J
CJ
Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.|Veterinary Medicine Extension, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.
Adams
Sean
S
Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.
Yang
Zengqi
Z
College of Veterinary Medicine, Northwest A & F University, Yangling 712100, PR China.
Li
Jinling
J
Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.
Perez
Daniel
D
Department of Veterinary Medicine, University of Maryland at College Park and Virginia-Maryland Regional College of Veterinary Medicine, College Park, MD 20742, USA.
Woolcock
Peter R
PR
California Animal Health and Food Safety Laboratory System-Fresno Branch, University of California, Davis, CA 95616, USA.|Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002645:Chickens; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D053222:Fas Ligand Protein / Q000378:metabolism; D015967:Gene Expression Regulation, Viral / Q000502:physiology; D053127:Influenza A Virus, H9N2 Subtype; D005585:Influenza in Birds / Q000821:virology; D008264:Macrophages / Q000378:metabolism* / Q000821:virology; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
D016207:Cytokines; D053222:Fas Ligand Protein; C085820:INS1 protein, influenza virus; D017361:Viral Nonstructural Proteins; D019014:fas Receptor