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.