학술논문
Identification of FasL as a crucial host factor driving COVID-19 pathology and lethality
Document Type
Original Paper
Author
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; Monzón, Marta; Badiola, Juan J.; Reindl-Schwaighofer, Roman; Sanz-Pamplona, Rebeca; Cebollada-Solanas, Alberto; Megyesfalvi, Zsolt; Dome, Balazs; Secrier, Maria; Hartmann, Boris; Bergmann, Michael; Pardo, Julián; Walczak, Henning
Source
Cell Death & Differentiation: Official journal of the ADMC Associazione Differenziamento e Morte Cellulare. 31(5):544-557
Subject
Language
English
ISSN
1350-9047
1476-5403
1476-5403
Abstract
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.