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

Albert, Marie-Christine and Uranga-Murillo, Iratxe and Arias, Maykel and De Miguel, Diego and Peña, Natacha and Montinaro, Antonella and Varanda, Ana Beatriz and Theobald, Sebastian J. and Areso, Itziar and Saggau, Julia and Koch, Manuel and Liccardi, Gianmaria and Peltzer, Nieves and Rybniker, Jan and Hurtado-Guerrero, Ramón and Merino, Pedro and Monzón, Marta and Badiola, Juan J. and Reindl-Schwaighofer, Roman and Sanz-Pamplona, Rebeca and Cebollada-Solanas, Alberto and Megyesfalvi, Zsolt and Dome, Balazs and Secrier, Maria and Hartmann, Boris and Bergmann, Michael and Pardo, Julián and Walczak, Henning (2024) Identification of FasL as a crucial host factor driving COVID-19 pathology and lethality. Cell Death & Differentiation, 31 (5). pp. 544-557. ISSN 1350-9047

Preview

Text s41418-024-01278-6.pdf - Published Version Available under License Creative Commons Attribution. Download (6MB) | Preview

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

Actions (login required)

Edit Item