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

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

doi:10.1038/s41418-024-01278-6

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

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

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

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.

Original language	English
Pages (from-to)	544-557
Number of pages	14
Journal	Cell Death and Differentiation
Volume	31
Issue number	5
DOIs	https://doi.org/10.1038/s41418-024-01278-6
State	Published - May 2024
Externally published	Yes

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Albert, M. C., Uranga-Murillo, I., Arias, M., De Miguel, D., Peña, N., Montinaro, A., Varanda, A. B., Theobald, S. J., Areso, I., Saggau, J., Koch, M., Liccardi, G., Peltzer, N., Rybniker, J., Hurtado-Guerrero, R., Merino, P., Monzón, M., Badiola, J. J., Reindl-Schwaighofer, R., ... Walczak, H. (2024). Identification of FasL as a crucial host factor driving COVID-19 pathology and lethality. Cell Death and Differentiation, 31(5), 544-557. https://doi.org/10.1038/s41418-024-01278-6

@article{da5d430df285483ca63f4494db2285c0,

title = "Identification of FasL as a crucial host factor driving COVID-19 pathology and lethality",

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.",

author = "Albert, {Marie Christine} and Iratxe Uranga-Murillo and Maykel Arias and {De Miguel}, Diego and Natacha Pe{\~n}a and Antonella Montinaro and Varanda, {Ana Beatriz} and Theobald, {Sebastian J.} and Itziar Areso and Julia Saggau and Manuel Koch and Gianmaria Liccardi and Nieves Peltzer and Jan Rybniker and Ram{\'o}n Hurtado-Guerrero and Pedro Merino and Marta Monz{\'o}n and Badiola, {Juan J.} and Roman Reindl-Schwaighofer and Rebeca Sanz-Pamplona and Alberto Cebollada-Solanas and Zsolt Megyesfalvi and Balazs Dome and Maria Secrier and Boris Hartmann and Michael Bergmann and Juli{\'a}n Pardo and Henning Walczak",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = may,

doi = "10.1038/s41418-024-01278-6",

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Albert, MC, Uranga-Murillo, I, Arias, M, De Miguel, D, Peña, N, Montinaro, A, Varanda, AB, Theobald, SJ, Areso, I, Saggau, J, Koch, M, Liccardi, G, Peltzer, N, Rybniker, J, Hurtado-Guerrero, R, Merino, P, Monzón, M, Badiola, JJ, Reindl-Schwaighofer, R, Sanz-Pamplona, R, Cebollada-Solanas, A, Megyesfalvi, Z, Dome, B, Secrier, M, Hartmann, B, Bergmann, M, Pardo, J & Walczak, H 2024, 'Identification of FasL as a crucial host factor driving COVID-19 pathology and lethality', Cell Death and Differentiation, vol. 31, no. 5, pp. 544-557. https://doi.org/10.1038/s41418-024-01278-6

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

PY - 2024/5

Y1 - 2024/5

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.

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DO - 10.1038/s41418-024-01278-6

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SP - 544

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JO - Cell Death and Differentiation

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ER -

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

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