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Monocyte-driven atypical cytokine storm and aberrant neutrophil activation as key mediators of COVID-19 disease severity

2021; Nature Portfolio; Volume: 12; Issue: 1 Linguagem: Inglês

10.1038/s41467-021-24360-w

2041-1723

Lore Vanderbeke, Pierre Van Mol, Yannick Van Herck, Frederik De Smet, Stéphanie Humblet‐Baron, Kimberly Martinod, Asier Antoranz, Ingrid Arijs, Bram Boeckx, Francesca M. Bosisio, Michaël P. Casaer, Dieter Dauwe, Walter De Wever, Christophe Dooms, Erwin Dreesen, Annelies Emmaneel, Jessica Filtjens, Mieke Gouwy, Jan Gunst, Greet Hermans, Sander Jansen, Katrien Lagrou, Adrian Liston, Natalie Lorent, Philippe Meersseman, Toine Mercier, Johan Neyts, Julie Odent, Dena Panovska, Pier-Andrée Penttilä, Émeline Pollet, Paul Proost, Junbin Qian, Katrien Quintelier, Jeroen Raes, S. Rex, Yvan Saeys, Jenny Sprooten, Sabine Tejpar, Dries Testelmans, Karin Thevissen, Tina Van Buyten, Jessica Vandenhaute, Sofie Van Gassen, Leydi Carolina Velásquez Pereira, Robin Vos, Birgit Weynand, A. Wilmer, Jonas Yserbyt, Abhishek D. Garg, Patrick Matthys, Carine Wouters, Diether Lambrechts, Els Wauters, Joost Wauters,

Inflammasome and immune disorders

Epidemiological and clinical reports indicate that SARS-CoV-2 virulence hinges upon the triggering of an aberrant host immune response, more so than on direct virus-induced cellular damage. To elucidate the immunopathology underlying COVID-19 severity, we perform cytokine and multiplex immune profiling in COVID-19 patients. We show that hypercytokinemia in COVID-19 differs from the interferon-gamma-driven cytokine storm in macrophage activation syndrome, and is more pronounced in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels paired with deep-immune profiling shows that classical monocytes drive this hyper-inflammatory phenotype and that a reduction in T-lymphocytes correlates with disease severity, with CD8+ cells being disproportionately affected. Antigen presenting machinery expression is also reduced in critical disease. Furthermore, we report that neutrophils contribute to disease severity and local tissue damage by amplification of hypercytokinemia and the formation of neutrophil extracellular traps. Together our findings suggest a myeloid-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity.