Bax-dependent mitochondrial membrane permeabilization enhances IRF3-mediated innate immune response during VSV infection.
An effective type I interferon (IFN-alpha/beta) response is critical for the control of many viral infections. Using an oncolytic strain of vesicular stomatitis virus, we have examined the cross-talk between virus-induced apoptosis and initiation of innate immune response. The intrinsic apoptotic cascade, specifically the Bax-Bcl-2-Caspase-9 cascade, was revealed as the primary pathway of VSV-induced apoptosis. Cell death was significantly reduced in BaxBak(-/-) murine embryonic fibroblasts (MEFs) and in human A549 epithelial cells treated with siRNA against Bax. Although inhibition of apoptosis resulted in enhanced virus replication in the BaxBak(-/-) MEFs as compared to wild-type cells, induction of the IFN antiviral response and expression of cytokine genes were attenuated in virus-infected cells. Moreover, Bax but not Bak pro-apoptotic protein was required for IRF-3 phosphorylation and activation, further substantiating a role for the intrinsic mitochondrial pathway in the innate immune response. Therefore, virus-induced apoptosis through a Bax-dependent mitochondrial pathway appears to enhance the full development of the IRF-3 mediated IFN antiviral response.
Sharif-Askari
Ehssan
E
Molecular Oncology Group, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
Nakhaei
Peyman
P
Oliere
Stephanie
S
Tumilasci
Vanessa
V
Hernandez
Eduardo
E
Wilkinson
Peter
P
Lin
Rongtuan
R
Bell
John
J
Hiscott
John
J
D000818:Animals; D018929:Cell Culture Techniques; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000502:physiology*; D008928:Mitochondria / Q000187:drug effects; D024101:Mitochondrial Proteins / Q000378:metabolism; D018353:Rhabdoviridae Infections / Q000276:immunology*; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology* / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000502:physiology*
C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D024101:Mitochondrial Proteins; D051028:bcl-2-Associated X Protein