Abstract
Mechanisms of neutrophil involvement in severe coronavirus disease 2019 (COVID-19) remain incompletely understood. Here, we collect longitudinal blood samples from 306 hospitalized COVID-19 + 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.
Keywords: COVID-19; G-MDSC; IgA; NETosis; SARS-CoV-2; degranulation; neutrophil; transcriptomics.
【저자키워드】 COVID-19, SARS-CoV-2, neutrophil, IgA, NETosis, G-MDSC, transcriptomics., degranulation, 【초록키워드】 Neutrophils, coronavirus, Mortality, severe COVID-19, disease severity, transcriptomics, IgG antibody, Humoral response, Immunoglobulin, response, RNA sequencing, Patient, Control, plasma, phagocytosis, Severe patient, experiment, cell death, disease, plasma proteomics, antibody profiling, severe disease, Subtypes, acute respiratory syndrome, severe coronavirus disease, blood sample, functions, gene expression signature, hospitalized COVID-19, healthy donor, Granulocytic, identify, elevated, induce, contributing to, dysregulated, survived, IgA antibody, driver, 【제목키워드】 severity, phenotype, longitudinal, hospitalized COVID-19 patient, circulating neutrophil,