Lack of Bax prevents influenza A virus-induced apoptosis and causes diminished viral replication.
The ectopic overexpression of Bcl-2 restricts both influenza A virus-induced apoptosis and influenza A virus replication in MDCK cells, thus suggesting a role for Bcl-2 family members during infection. Here we report that influenza A virus cannot establish an apoptotic response without functional Bax, a downstream target of Bcl-2, and that both Bax and Bak are directly involved in influenza A virus replication and virus-induced cell death. Bak is substantially downregulated during influenza A virus infection in MDCK cells, and the knockout of Bak in mouse embryonic fibroblasts yields a dramatic rise in the rate of apoptotic death and a corresponding increase in levels of virus replication, suggesting that Bak suppresses both apoptosis and the replication of virus and that the virus suppresses Bak. Bax, however, is activated and translocates from the cytosol to the mitochondria; this activation is required for the efficient induction of apoptosis and virus replication. The knockout of Bax in mouse embryonic fibroblasts blocks the induction of apoptosis, restricts the infection-mediated activation of executioner caspases, and inhibits virus propagation. Bax knockout cells still die but by an alternative death pathway displaying characteristics of autophagy, similarly to our previous observation that influenza A virus infection in the presence of a pancaspase inhibitor leads to an increase in levels of autophagy. The knockout of Bax causes a retention of influenza A virus NP within the nucleus. We conclude that the cell and virus struggle to control apoptosis and autophagy, as appropriately timed apoptosis is important for the replication of influenza A virus.
McLean
Jeffrey E
JE
Department of Biology, Queens College and Graduate Center of the City University of New York, Flushing, New York 11367, USA.
Datan
Emmanuel
E
Matassov
Demetrius
D
Zakeri
Zahra F
ZF
D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004285:Dogs; D006801:Humans; D009980:Influenza A virus / Q000235:genetics / Q000502:physiology*; D007251:Influenza, Human / Q000378:metabolism* / Q000503:physiopathology* / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D021381:Protein Transport; D014779:Virus Replication; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
D051028:bcl-2-Associated X Protein; D020169:Caspases