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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 and Saggau, Julia , et al. (2024) In Cell Death and Differentiation
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... (More)

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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organization
publishing date
type
Contribution to journal
publication status
in press
subject
in
Cell Death and Differentiation
publisher
Nature Publishing Group
external identifiers
  • pmid:38514848
  • scopus:85188232748
ISSN
1350-9047
DOI
10.1038/s41418-024-01278-6
language
English
LU publication?
yes
id
21c4679c-1fc0-4dc6-803e-e72be02a624b
date added to LUP
2024-04-09 13:23:33
date last changed
2024-04-23 16:15:25
@article{21c4679c-1fc0-4dc6-803e-e72be02a624b,
  abstract     = {{<p>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.</p>}},
  author       = {{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}},
  issn         = {{1350-9047}},
  language     = {{eng}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Cell Death and Differentiation}},
  title        = {{Identification of FasL as a crucial host factor driving COVID-19 pathology and lethality}},
  url          = {{http://dx.doi.org/10.1038/s41418-024-01278-6}},
  doi          = {{10.1038/s41418-024-01278-6}},
  year         = {{2024}},
}