Longitudinal characterization of circulating neutrophils uncovers phenotypes associated with severity in hospitalized COVID-19 patients
Thomas J. LaSalle, Anna Gonye, Samuel S. Freeman, Paulina Kapłonek, Irena Gushterova, Kyle R. Kays, Kasidet Manakongtreecheep, Jessica Tantivit, Maricarmen Rojas-López, Brian C. Russo, Nihaarika Sharma, Molly Thomas, Kendall M. Lavin-Parsons, Brendan M. Lilly, Brenna McKaig, Nicole C. Charland, Hargun K. Khanna, Carl L. Lodenstein, Justin Margolin, Emily M. Blaum, Paola B. Lirofonis, Or‐Yam Revach, Arnav Mehta, Abraham Sonny, Roby P. Bhattacharyya, Blair A. Parry, Marcia B. Goldberg, Galit Alter, Michael R. Filbin, Alexandra–Chloé Villani, Nir Hacohen, Moshe Sade-Feldman
Abstract
patients and 86 controls and perform bulk RNA sequencing of enriched neutrophils, plasma proteomics, and high-throughput antibody profiling to investigate relationships between neutrophil states and disease severity. We identify dynamic switches between six distinct neutrophil subtypes. At days 3 and 7 post-hospitalization, patients with severe disease display a granulocytic myeloid-derived suppressor cell-like gene expression signature, while patients with resolving disease show a neutrophil progenitor-like signature. Humoral responses are identified as potential drivers of neutrophil effector functions, with elevated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific immunoglobulin G1 (IgG1)-to-IgA1 ratios in plasma of severe patients who survived. In vitro experiments confirm that while patient-derived IgG antibodies induce phagocytosis in healthy donor neutrophils, IgA antibodies predominantly induce neutrophil cell death. Overall, our study demonstrates a dysregulated myelopoietic response in severe COVID-19 and a potential role for IgA-dominant responses contributing to mortality.