Pathogenic neutrophilia drives acute respiratory distress syndrome in severe COVID-19 patients

Eddins, D. J.; Yang, J.; Kosters, A.; Giacalone, V.; Pechuan, X.; Chandler, J. D.; Babcock, B. R.; Eum, J.; Hernandez, M. R.; Abdulkhader, F.; Collins, G. L.; Ramonell, R. P.; Moussion, C.; Orlova, D.; Sanz, I.; Lee, F. E.-H.; Tirouvanziam, R.; Ghosn, E.

doi:10.1101/2021.06.02.446468

bioRxiv · 10.1101/2021.06.02.446468

Pathogenic neutrophilia drives acute respiratory distress syndrome in severe COVID-19 patients

Eddins, D. J.·Yang, J.·Kosters, A.·Giacalone, V.·Pechuan, X.·Chandler, J. D.·Babcock, B. R.·Eum, J.·Hernandez, M. R.·Abdulkhader, F.·Collins, G. L.·Ramonell, R. P.·Moussion, C.·Orlova, D.·Sanz, I.·Lee, F. E.-H.·Tirouvanziam, R.·Ghosn, E.

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Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the ensuing COVID-19 pandemic have caused [~]40 million cases and over 648,000 deaths in the United States alone. Troubling disparities in COVID-19-associated mortality emerged early, with nearly 70% of deaths confined to Black/African-American (AA) patients in some areas, yet targeted studies within this demographic are scant. Multi-omics single-cell analyses of immune profiles from airways and matching blood samples of Black/AA patients revealed low viral load, yet pronounced and persistent pulmonary neutrophilia with advanced features of cytokine release syndrome and acute respiratory distress syndrome (ARDS), including exacerbated production of IL-8, IL-1{beta}, IL-6, and CCL3/4 along with elevated levels of neutrophil elastase and myeloperoxidase. Circulating S100A12+/IFITM2+ mature neutrophils are recruited via the IL-8/CXCR2 axis, which emerges as a potential therapeutic target to reduce pathogenic neutrophilia and constrain ARDS in severe COVID-19. Graphical AbstractThe lung pathology due to severe COVID-19 is marked by a perpetual pathogenic neutrophilia, leading to acute respiratory distress syndrome (ARDS) even in the absence of viral burden. Circulating mature neutrophils are recruited to the airways via IL-8 (CXCL8)/CXCR2 chemotaxis. Recently migrated neutrophils further differentiate into a transcriptionally active and hyperinflammatory state, with an exacerbated expression of IL-8 (CXCL8), IL-1{beta} (IL1B), CCL3, CCL4, neutrophil elastase (NE), and myeloperoxidase (MPO) activity. Airway neutrophils and recruited inflammatory monocytes further increase their production of IL-8 (CXCL8), perpetuating lung neutrophilia in a feedforward loop. MdCs and T cells produce IL-1{beta} and TNF, driving neutrophils reprogramming and survival. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/446468v2_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@81fd3aorg.highwire.dtl.DTLVardef@181e63org.highwire.dtl.DTLVardef@172fedcorg.highwire.dtl.DTLVardef@ba55a7_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Eddins, D. J., Yang, J., Kosters, A., Giacalone, V., Pechuan, X., Chandler, J. D., Babcock, B. R., Eum, J., Hernandez, M. R., Abdulkhader, F., Collins, G. L., Ramonell, R. P., Moussion, C., Orlova, D., Sanz, I., Lee, F. E.-H., Tirouvanziam, R., Ghosn, E.. 2021-06-03. Pathogenic neutrophilia drives acute respiratory distress syndrome in severe COVID-19 patients. https://doi.org/10.1101/2021.06.02.446468

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