TY - JOUR

T1 - Identification of FasL as a crucial host factor driving COVID-19 pathology and lethality

AU - Albert, Marie Christine

AU - Uranga-Murillo, Iratxe

AU - Arias, Maykel

AU - De Miguel, Diego

AU - Peña, Natacha

AU - Montinaro, Antonella

AU - Varanda, Ana Beatriz

AU - Theobald, Sebastian J.

AU - Areso, Itziar

AU - Saggau, Julia

AU - Koch, Manuel

AU - Liccardi, Gianmaria

AU - Peltzer, Nieves

AU - Rybniker, Jan

AU - Hurtado-Guerrero, Ramón

AU - Merino, Pedro

AU - Monzón, Marta

AU - Badiola, Juan J.

AU - Reindl-Schwaighofer, Roman

AU - Sanz-Pamplona, Rebeca

AU - Cebollada-Solanas, Alberto

AU - Megyesfalvi, Zsolt

AU - Dome, Balazs

AU - Secrier, Maria

AU - Hartmann, Boris

AU - Bergmann, Michael

AU - Pardo, Julián

AU - Walczak, Henning

N1 - Publisher Copyright: © The Author(s) 2024.

PY - 2024

Y1 - 2024

N2 - 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.

AB - 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.

U2 - 10.1038/s41418-024-01278-6

DO - 10.1038/s41418-024-01278-6

M3 - Journal article

C2 - 38514848

AN - SCOPUS:85188232748

VL - 31

SP - 544

EP - 557

JO - Cell Differentiation and Development

JF - Cell Differentiation and Development

SN - 1350-9047

ER -