Identification of FasL as a crucial host factor driving COVID-19 pathology and lethality

Albert, Marie-Christine ; Uranga-Murillo, Iratxe ; Arias, Maykel ; De Miguel, Diego ; Peña, Natacha ; Montinaro, Antonella ; Varanda, Ana Beatriz ; Theobald, Sebastian J. ; Areso, Itziar ; Saggau, Julia ; Koch, Manuel ; Liccardi, Gianmaria ; Peltzer, Nieves ; Rybniker, Jan ; Hurtado-Guerrero, Ramón ; Merino, Pedro (Universidad de Zaragoza) ; Monzón, Marta (Universidad de Zaragoza) ; Badiola, Juan J. (Universidad de Zaragoza) ; Reindl-Schwaighofer, Roman ; Sanz-Pamplona, Rebeca ; Cebollada-Solanas, Alberto ; Megyesfalvi, Zsolt ; Dome, Balazs ; Secrier, Maria ; Hartmann, Boris ; Bergmann, Michael ; Pardo, Julián (Universidad de Zaragoza) ; Walczak, Henning

Resumen: The 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.

Idioma: Inglés

DOI: 10.1038/s41418-024-01278-6

Año: 2024

Publicado en: Cell Death and Differentiation 31 (2024), 544–557
ISSN: 1350-9047

Financiación: info:eu-repo/grantAgreement/ES/AEI/PID2019-104090RB-I00
Financiación: info:eu-repo/grantAgreement/ES/AEI/PID2020-113963RB-I00
Financiación: info:eu-repo/grantAgreement/ES/DGA/B29-20R
Financiación: info:eu-repo/grantAgreement/ES/DGA/E34-17R
Financiación: info:eu-repo/grantAgreement/ES/DGA/LMP58-18
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/CB21-13-00087
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/COV20-00308
Financiación: info:eu-repo/grantAgreement/ES/MICINN AEI/PID2022-136362NB-I00

Tipo y forma: Article (Published version)

Área (Departamento): Area Histología (Dpto. Anatom.Histolog.Humanas)
Área (Departamento): Área Sanidad Animal (Dpto. Patología Animal)
Área (Departamento): Área Inmunología (Dpto. Microb.Ped.Radio.Sal.Pú.)
Área (Departamento): Área Química Orgánica (Dpto. Química Orgánica)