tetano
Editor, Senior Moderator
J Mol Med (Berl)
. 2025 Dec 26;104(1):17.
doi: 10.1007/s00109-025-02627-9. The cell death regulator c-FLIP[SUB]R[/SUB] impairs natural killer cell responses during influenza a virus infection
André Carmo-Fernandes[SUP] #[/SUP][SUP] 1 [/SUP], Neda Tafrishi[SUP] #[/SUP][SUP] 2 [/SUP], Clara Bessen[SUP] 1 [/SUP], Konstantinos Katsoulis-Dimitriou[SUP] 3 [/SUP], Marina C Greweling-Pils[SUP] 4 [/SUP], Dunja Bruder[SUP] 5 6 [/SUP], Carlos Plaza-Sirvent[SUP] #[/SUP][SUP] 1 [/SUP], Ingo Schmitz[SUP] #[/SUP][SUP] 7 [/SUP]
Affiliations
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[SUB]long[/SUB] and c-FLIP[SUB]short[/SUB] are well characterized, the function of c-FLIP[SUB]R[/SUB] remains poorly understood. To study the role of c-FLIP[SUB]R[/SUB] in influenza A virus (IAV) infection, we employed vavFLIP[SUB]R[/SUB] transgenic mice that constitutively express murine c-FLIP[SUB]R[/SUB] in all hematopoietic cells. Upon IAV challenge, vavFLIP[SUB]R[/SUB] 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[SUB]R[/SUB] and control mice were equally able to kill tumor cells in vitro, we detected reduced degranulation of c-FLIP[SUB]R[/SUB] transgenic NK cells from infected mice compared to wild-type counterparts. Furthermore, TNFα and IFNg expression was reduced in c-FLIP[SUB]R[/SUB] transgenic NK cells. We conclude that c-FLIP[SUB]R[/SUB] impairs NK cell activity during IAV infection. KEY MESSAGES: Constitutive expression of the anti-apoptotic c-FLIP[SUB]R[/SUB] in hematopoietic cells increases IAV titers. Accumulation of NK cells in vavFLIP[SUB]R[/SUB] mice during IAV infection. IAV infects NK cells in a non-productive manner. IAV infection of NK cells impairs their function.
Keywords: Apoptosis; Influenza A virus; Natural killer cells; c-FLIP.
. 2025 Dec 26;104(1):17.
doi: 10.1007/s00109-025-02627-9. The cell death regulator c-FLIP[SUB]R[/SUB] impairs natural killer cell responses during influenza a virus infection
André Carmo-Fernandes[SUP] #[/SUP][SUP] 1 [/SUP], Neda Tafrishi[SUP] #[/SUP][SUP] 2 [/SUP], Clara Bessen[SUP] 1 [/SUP], Konstantinos Katsoulis-Dimitriou[SUP] 3 [/SUP], Marina C Greweling-Pils[SUP] 4 [/SUP], Dunja Bruder[SUP] 5 6 [/SUP], Carlos Plaza-Sirvent[SUP] #[/SUP][SUP] 1 [/SUP], Ingo Schmitz[SUP] #[/SUP][SUP] 7 [/SUP]
Affiliations
- PMID: 41453987
- DOI: 10.1007/s00109-025-02627-9
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[SUB]long[/SUB] and c-FLIP[SUB]short[/SUB] are well characterized, the function of c-FLIP[SUB]R[/SUB] remains poorly understood. To study the role of c-FLIP[SUB]R[/SUB] in influenza A virus (IAV) infection, we employed vavFLIP[SUB]R[/SUB] transgenic mice that constitutively express murine c-FLIP[SUB]R[/SUB] in all hematopoietic cells. Upon IAV challenge, vavFLIP[SUB]R[/SUB] 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[SUB]R[/SUB] and control mice were equally able to kill tumor cells in vitro, we detected reduced degranulation of c-FLIP[SUB]R[/SUB] transgenic NK cells from infected mice compared to wild-type counterparts. Furthermore, TNFα and IFNg expression was reduced in c-FLIP[SUB]R[/SUB] transgenic NK cells. We conclude that c-FLIP[SUB]R[/SUB] impairs NK cell activity during IAV infection. KEY MESSAGES: Constitutive expression of the anti-apoptotic c-FLIP[SUB]R[/SUB] in hematopoietic cells increases IAV titers. Accumulation of NK cells in vavFLIP[SUB]R[/SUB] mice during IAV infection. IAV infects NK cells in a non-productive manner. IAV infection of NK cells impairs their function.
Keywords: Apoptosis; Influenza A virus; Natural killer cells; c-FLIP.