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

• Published in: Nature communications Vol. 12; no. 1; p. 4117
• Main Authors: Vanderbeke, L., Van Mol, P., Van Herck, Y., De Smet, F., Humblet-Baron, S., Martinod, K., Antoranz, A., Arijs, I., Boeckx, B., Bosisio, F. M., Casaer, M., Dauwe, D., De Wever, W., Dooms, C., Dreesen, E., Emmaneel, A., Filtjens, J., Gouwy, M., Gunst, J., Hermans, G., Jansen, S., Lagrou, K., Liston, A., Lorent, N., Meersseman, P., Mercier, T., Neyts, J., Odent, J., Panovska, D., Penttila, P. A., Pollet, E., Proost, P., Qian, J., Quintelier, K., Raes, J., Rex, S., Saeys, Y., Sprooten, J., Tejpar, S., Testelmans, D., Thevissen, K., Van Buyten, T., Vandenhaute, J., Van Gassen, S., Velásquez Pereira, L. C., Vos, R., Weynand, B., Wilmer, A., Yserbyt, J., Garg, A. D., Matthys, P., Wouters, C., Lambrechts, D., Wauters, E., Wauters, J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.07.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/21; 13/31; 38/91; 631/250/254; 631/250/255/2514; 631/326/596/4130; 692/420/254; 82/80; Adaptive systems; Aged; Antigen-Presenting Cells - immunology; Antigens; Case-Control Studies; CD8 antigen; Cell activation; Coronaviruses; COVID-19; COVID-19 - blood; COVID-19 - complications; COVID-19 - immunology; COVID-19 - virology; Cytokine Release Syndrome - blood; Cytokine Release Syndrome - complications; Cytokine Release Syndrome - pathology; Cytokine Release Syndrome - virology; Cytokine storm; Cytokines; Cytokines - blood; Damage; Depth profiling; Epidemiology; Extracellular Traps - metabolism; Female; Histocompatibility Antigens Class II - metabolism; Humanities and Social Sciences; Humans; Immune response; Immune system; Immunophenotyping; Inflammation; Interferon; Leukocytes (neutrophilic); Lymphocytes; Lymphocytes T; Macrophages; Male; Middle Aged; Monocytes; Monocytes - pathology; multidisciplinary; Neutrophil Activation; Neutrophils; Phenotypes; SARS-CoV-2 - physiology; Science; Science (multidisciplinary); Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Severity of Illness Index; Viral diseases; Virulence; Viruses; γ-Interferon
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-24360-w

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. The host immune response plays a critical role in the immunopathology of SARS-CoV2. Here the authors combine a systems biology approach to implicate monocytes as key drivers of cytokine storm and disturbed neutrophil activation in COVID-19 disease severity.