Transcriptional reprogramming of infiltrating neutrophils drives lung pathology in severe COVID-19 despite low viral load
Devon J. Eddins, Junkai Yang, Astrid Kosters, Vincent D. Giacalone, Ximo Pechuan-Jorge, Joshua D. Chandler, Jinyoung Eum, Benjamin Babcock, Brian Dobosh, Mindy Hernandez, Fathma Abdulkhader, Genoah Collins, Darya Orlova, Richard P. Ramonell, Igñacio Sanz, Christine Moussion, F. Eun-Hyung Lee, Rabindra Tirouvanziam, Eliver Ghosn
Abstract
Troubling disparities in COVID-19-associated mortality emerged early, with nearly 70% of deaths confined to Black/African American (AA) patients in some areas. However, targeted studies on this vulnerable population are scarce. Here, we applied multiomics single-cell analyses of immune profiles from matching airways and blood samples of Black/AA patients during acute SARS-CoV-2 infection. Transcriptional reprogramming of infiltrating IFITM2+/S100A12+ mature neutrophils, likely recruited via the IL-8/CXCR2 axis, leads to persistent and self-sustaining pulmonary neutrophilia with advanced features of acute respiratory distress syndrome (ARDS) despite low viral load in the airways. In addition, exacerbated neutrophil production of IL-8, IL-1β, IL-6, and CCL3/4, along with elevated levels of neutrophil elastase and myeloperoxidase, were the hallmarks of transcriptionally active and pathogenic airway neutrophilia. Although our analysis was limited to Black/AA patients and was not designed as a comparative study across different ethnicities, we present an unprecedented in-depth analysis of the immunopathology that leads to acute respiratory distress syndrome in a well-defined patient population disproportionally affected by severe COVID-19.