The cell death regulator c-FLIPR impairs natural killer cell responses during influenza a virus infection.

Apoptosis, a form of programmed cell death, is crucial for keeping homeostasis during and after infections. Cellular FLICE-inhibitory protein (c-FLIP) is an inhibitor of death receptor-mediated apoptosis, of which three isoforms have been characterized so far. While the isoforms c-FLIPlong and c-FLIPshort are well characterized, the function of c-FLIPR remains poorly understood. To study the role of c-FLIPR in influenza A virus (IAV) infection, we employed vavFLIPR transgenic mice that constitutively express murine c-FLIPR in all hematopoietic cells. Upon IAV challenge, vavFLIPR mice showed an altered viral dynamic with a higher viral load than wild-type mice, coinciding with a higher number of Natural Killer (NK) cells. IAV directly infected murine NK cells, but viral particles produced by NK cells did not infect other target cells. While NK cells from vavFLIPR and control mice were equally able to kill tumor cells in vitro, we detected reduced degranulation of c-FLIPR transgenic NK cells from infected mice compared to wild-type counterparts. Furthermore, TNFα and IFNg expression was reduced in c-FLIPR transgenic NK cells. We conclude that c-FLIPR impairs NK cell activity during IAV infection. KEY MESSAGES: Constitutive expression of the anti-apoptotic c-FLIPR in hematopoietic cells increases IAV titers. Accumulation of NK cells in vavFLIPR mice during IAV infection. IAV infects NK cells in a non-productive manner. IAV infection of NK cells impairs their function.