Longitudinal characterization of circulating neutrophils uncovers distinct phenotypes associated with severity in hospitalized COVID-19 patients

Mechanisms of neutrophil involvement in severe 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 profi...

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Published in:Cell reports. Medicine 2022-09
Main Authors: LaSalle, Thomas J., Gonye, Anna L.K., Freeman, Samuel S., Kaplonek, Paulina, Gushterova, Irena, Kays, Kyle R., Manakongtreecheep, Kasidet, Tantivit, Jessica, Rojas-Lopez, Maricarmen, Russo, Brian C., Sharma, Nihaarika, Thomas, Molly F., Lavin-Parsons, Kendall M., Lilly, Brendan M., Mckaig, Brenna N., Charland, Nicole C., Khanna, Hargun K., Lodenstein, Carl L., Margolin, Justin D., Blaum, Emily M., Lirofonis, Paola B., Revach, Or-Yam, Mehta, Arnav, Sonny, Abraham, Bhattacharyya, Roby P., Parry, Blair Alden, Goldberg, Marcia B., Alter, Galit, Filbin, Michael R., Villani, Alexandra Chloe, Hacohen, Nir, Sade-Feldman, Moshe
Format: Article
Language:English
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Summary:Mechanisms of neutrophil involvement in severe 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 6 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 SARS-CoV-2-specific 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. LaSalle et al. utilize bulk transcriptomics of neutrophils, plasma proteomics, and high-throughput antibody profiling of a large cohort of hospitalized COVID-19 patients to explore the relationship between neutrophil states and disease severity. They identify granulocytic myeloid-derived suppressor cell-like signatures and plasma IgA1-to-IgG1 ratios as predictive of disease severity and mortality.
ISSN:2666-3791
DOI:10.1016/j.xcrm.2022.100779