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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\n                      <jats:sub>long<\/jats:sub>\n                      and c-FLIP\n                      <jats:sub>short<\/jats:sub>\n                      are well characterized, the function of c-FLIP\n                      <jats:sub>R<\/jats:sub>\n                      remains poorly understood. To study the role of c-FLIP\n                      <jats:sub>R<\/jats:sub>\n                      in influenza A virus (IAV) infection, we employed vavFLIP\n                      <jats:sub>R<\/jats:sub>\n                      transgenic mice that constitutively express murine c-FLIP\n                      <jats:sub>R<\/jats:sub>\n                      in all hematopoietic cells. Upon IAV challenge, vavFLIP\n                      <jats:sub>R<\/jats:sub>\n                      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\n                      <jats:sub>R<\/jats:sub>\n                      and control mice were equally able to kill tumor cells in vitro, we detected reduced degranulation of c-FLIP\n                      <jats:sub>R<\/jats:sub>\n                      transgenic NK cells from infected mice compared to wild-type counterparts. Furthermore, TNF\u03b1 and IFNg expression was reduced in c-FLIP\n                      <jats:sub>R<\/jats:sub>\n                      transgenic NK cells. We conclude that c-FLIP\n                      <jats:sub>R<\/jats:sub>\n                      impairs NK cell activity during IAV infection.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key messages<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>\n                            Constitutive expression of the anti-apoptotic c-FLIP\n                            <jats:sub>R<\/jats:sub>\n                            in hematopoietic cells increases IAV titers.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Accumulation of NK cells in vavFLIP\n                            <jats:sub>R<\/jats:sub>\n                            mice during IAV infection.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>IAV infects NK cells in a non-productive manner.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>IAV infection of NK cells impairs their function.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00109-025-02627-9","type":"journal-article","created":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T16:52:31Z","timestamp":1766767951000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The cell death regulator c-FLIPR impairs natural killer cell responses during influenza a virus infection"],"prefix":"10.1007","volume":"104","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4415-2298","authenticated-orcid":false,"given":"Andr\u00e9","family":"Carmo-Fernandes","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neda","family":"Tafrishi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1214-3012","authenticated-orcid":false,"given":"Clara","family":"Bessen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Konstantinos","family":"Katsoulis-Dimitriou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marina C.","family":"Greweling-Pils","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3066-189X","authenticated-orcid":false,"given":"Dunja","family":"Bruder","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2767-0402","authenticated-orcid":false,"given":"Carlos","family":"Plaza-Sirvent","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5360-0419","authenticated-orcid":false,"given":"Ingo","family":"Schmitz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,12,26]]},"reference":[{"key":"2627_CR1","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1038\/nrm2312","volume":"9","author":"RC Taylor","year":"2008","unstructured":"Taylor RC, Cullen SP, Martin SJ (2008) Apoptosis: controlled demolition at the cellular level. 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