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

• Published in: Cell death and differentiation Vol. 31; no. 5; pp. 544 - 557
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2024; Nature Publishing Group
• Subjects: 14/1; 631/250/1933; 631/250/256/2516; 64/60; 692/420/2780; 82/51; 96/2; 96/21; 96/31; Animals; Apoptosis; Basic Medicine; Biochemistry; Biomedical and Life Sciences; Bronchoalveolar Lavage Fluid; Bronchus; Cell Biology; Cell Cycle Analysis; Cell death; COVID-19; COVID-19 - immunology; COVID-19 - metabolism; COVID-19 - mortality; COVID-19 - pathology; COVID-19 - virology; Disease Models, Animal; Fas Ligand Protein - metabolism; FasL protein; Immune response; Immunologi inom det medicinska området (Här ingår: Cell- och immunterapi); Immunology in the Medical Area (including Cell and Immunotherapy); Inflammation; Inflammation - metabolism; Inflammation - pathology; Inflammatory diseases; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Lavage; Lethality; Life Sciences; Lung - metabolism; Lung - pathology; Lung - virology; Lung diseases; Lungs; Macrophages; Macrophages - metabolism; Macrophages - pathology; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Mice; Mice, Inbred C57BL; Monocytes; Pathology; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; Stem Cells
• ISSN: 1350-9047; 1476-5403; 1476-5403
• DOI: 10.1038/s41418-024-01278-6

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.