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-FLIP_long and c-FLIP_short are well characterized, the function of c-FLIP_R remains poorly understood. To study the role of c-FLIP_R in influenza A virus (IAV) infection, we employed vavFLIP_R transgenic mice that constitutively express murine c-FLIP_R in all hematopoietic cells. Upon IAV challenge, vavFLIP_R 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 vavFLIP_R and control mice were equally able to kill tumor cells in vitro, we detected reduced degranulation of c-FLIP_R transgenic NK cells from infected mice compared to wild-type counterparts. Furthermore, TNFα and IFNg expression was reduced in c-FLIP_R transgenic NK cells. We conclude that c-FLIP_R impairs NK cell activity during IAV infection. KEY MESSAGES: Constitutive expression of the anti-apoptotic c-FLIP_R in hematopoietic cells increases IAV titers. Accumulation of NK cells in vavFLIP_R mice during IAV infection. IAV infects NK cells in a non-productive manner. IAV infection of NK cells impairs their function.