doi:10.1038/s41418-024-01278-6engAlbert, Marie-ChristineUranga-Murillo, IratxeArias, MaykelDe Miguel, DiegoPeña, NatachaMontinaro, AntonellaVaranda, Ana BeatrizTheobald, Sebastian J.Areso, ItziarSaggau, JuliaKoch, ManuelLiccardi, GianmariaPeltzer, NievesRybniker, JanHurtado-Guerrero, RamónMerino, PedroMonzón, MartaBadiola, Juan J.Reindl-Schwaighofer, RomanSanz-Pamplona, RebecaCebollada-Solanas, AlbertoMegyesfalvi, ZsoltDome, BalazsSecrier, MariaHartmann, BorisBergmann, MichaelPardo, JuliánWalczak, HenningIdentification of FasL as a crucial host factor driving COVID-19 pathology and lethalityART-2024-138374The dysregulated immune response and inflammation resulting in severe COVID-19 are still incompletely understood. Having recently determined that aberrant death-ligand-induced cell death can cause lethal inflammation, we hypothesized that this process might also cause or contribute to inflammatory disease and lung failure following SARS-CoV-2 infection. To test this hypothesis, we developed a novel mouse-adapted SARS-CoV-2 model (MA20) that recapitulates key pathological features of COVID-19. Concomitantly with occurrence of cell death and inflammation, FasL expression was significantly increased on inflammatory monocytic macrophages and NK cells in the lungs of MA20-infected mice. Importantly, therapeutic FasL inhibition markedly increased survival of both, young and old MA20-infected mice coincident with substantially reduced cell death and inflammation in their lungs. Intriguingly, FasL was also increased in the bronchoalveolar lavage fluid of critically-ill COVID-19 patients. Together, these results identify FasL as a crucial host factor driving the immuno-pathology that underlies COVID-19 severity and lethality, and imply that patients with severe COVID-19 may significantly benefit from therapeutic inhibition of FasL.2024http://zaguan.unizar.es/record/13485810.1038/s41418-024-01278-6http://zaguan.unizar.es/record/134858oai:zaguan.unizar.es:134858info:eu-repo/grantAgreement/ES/AEI/PID2019-104090RB-I00info:eu-repo/grantAgreement/ES/AEI/PID2020-113963RB-I00info:eu-repo/grantAgreement/ES/DGA/B29-20Rinfo:eu-repo/grantAgreement/ES/DGA/E34-17Rinfo:eu-repo/grantAgreement/ES/DGA/LMP58-18info:eu-repo/grantAgreement/ES/ISCIII/CB21-13-00087info:eu-repo/grantAgreement/ES/ISCIII/COV20-00308info:eu-repo/grantAgreement/ES/MICINN AEI/PID2022-136362NB-I00Cell Death and Differentiation 31 (2024), 544–557byhttps://creativecommons.org/licenses/by/4.0/deed.esinfo:eu-repo/semantics/openAccess