TY - JOUR T1 - Pathogenic neutrophilia drives acute respiratory distress syndrome in severe COVID-19 patients JF - bioRxiv DO - 10.1101/2021.06.02.446468 SP - 2021.06.02.446468 AU - Devon J. Eddins AU - Junkai Yang AU - Astrid Kosters AU - Vincent D. Giacalone AU - Ximo Pechuan AU - Joshua D. Chandler AU - Benjamin R. Babcock AU - Jinyoung Eum AU - Mindy R. Hernández AU - Fathma Abdulkhader AU - Genoah L. Collins AU - Richard P. Ramonell AU - Christine Moussion AU - Darya Y. Orlova AU - Ignacio Sanz AU - F. Eun-Hyung Lee AU - Rabindra M. Tirouvanziam AU - Eliver E.B. Ghosn Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/06/03/2021.06.02.446468.abstract N2 - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the ensuing COVID-19 pandemic have caused ~33 million cases and over 585,000 deaths in the United States alone. Troubling disparities in COVID-19-associated mortality emerged early, with nearly 70% of deaths being Black/African-American (AA) patients in some areas, yet targeted studies to delineate features of disease severity within this demographic are scant. Our multi-omics single-cell analyses of immune profiles from airways and matching blood samples of Black/AA patients revealed pronounced pulmonary neutrophilia and low viral burden as a hallmark of severe disease, where neutrophil phenotypes display advanced features of cytokine release syndrome and acute respiratory distress syndrome (ARDS). Cell-cell communication and trajectory analysis reveal a subset of circulating S100A12+/CXCR4+ mature neutrophils that infiltrate the lung via the IL-8/CXCR2 axis. Recruited neutrophils progress toward a transcriptionally active and pathogenic state characterized by exacerbated production of IL-8, IL-1β, IL-6, and CCL3/4 along with elevated levels of neutrophil elastase and myeloperoxidase. Inflammatory monocytes recruited via neutrophil-derived CCL3/4 also produce elevated neutrophil chemotactic factor IL-8, potentiating the sustained neutrophilia in the airways. The IL-8/CXCR2 axis emerges as a potential therapeutic target to reduce pathogenic neutrophilia and constrain ARDS in severe COVID-19.Competing Interest StatementThe authors have declared no competing interest. ER -