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

Thomas J LaSalle; Anna L K Gonye; Samuel S Freeman; Paulina Kaplonek; Irena Gushterova; Kyle R Kays; Kasidet Manakongtreecheep; Jessica Tantivit; Maricarmen Rojas-Lopez; Brian C Russo; Nihaarika Sharma; Molly F Thomas; Kendall M Lavin-Parsons; Brendan M Lilly; Brenna N Mckaig; Nicole C Charland; Hargun K Khanna; Carl L Lodenstein; Justin D Margolin; Emily M Blaum; Paola B Lirofonis; Or-Yam Revach; Arnav Mehta; Abraham Sonny; Roby P Bhattacharyya; Blair Alden Parry; Marcia B Goldberg; Galit Alter; Michael R Filbin; Alexandra-Chloé Villani; Nir Hacohen; Moshe Sade-Feldman

doi:10.1016/j.xcrm.2022.100779

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

Cell Rep Med. 2022 Oct 18;3(10):100779. doi: 10.1016/j.xcrm.2022.100779. Epub 2022 Sep 26.

Authors

Thomas J LaSalle¹, Anna L K Gonye², Samuel S Freeman³, Paulina Kaplonek⁴, Irena Gushterova², Kyle R Kays⁵, Kasidet Manakongtreecheep⁶, Jessica Tantivit⁶, Maricarmen Rojas-Lopez⁷, Brian C Russo⁷, Nihaarika Sharma⁸, Molly F Thomas⁹, Kendall M Lavin-Parsons⁵, Brendan M Lilly⁵, Brenna N Mckaig⁵, Nicole C Charland⁵, Hargun K Khanna⁵, Carl L Lodenstein⁵, Justin D Margolin⁵, Emily M Blaum², Paola B Lirofonis⁸, Or-Yam Revach¹⁰, Arnav Mehta¹¹, Abraham Sonny¹², Roby P Bhattacharyya¹³, Blair Alden Parry⁵, Marcia B Goldberg¹⁴, Galit Alter⁴, Michael R Filbin¹⁵, Alexandra-Chloé Villani¹⁶, Nir Hacohen¹⁷, Moshe Sade-Feldman¹⁸

Affiliations

¹ Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Health Sciences and Technology, Harvard Medical School & Massachusetts Institute of Technology, Boston, MA, USA. Electronic address: tlasalle@broadinstitute.org.
² Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³ Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
⁴ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
⁵ Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁶ Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁷ Department of Medicine, Harvard Medical School, Boston, MA, USA; Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Department of Microbiology, Harvard Medical School, Boston, MA, USA.
⁸ Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁹ Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Department of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹⁰ Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
¹¹ Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹² Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹³ Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹⁴ Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Department of Microbiology, Harvard Medical School, Boston, MA, USA; Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁵ Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, USA; Department of Emergency Medicine, Harvard Medical School, Boston, MA, USA.
¹⁶ Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
¹⁷ Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA. Electronic address: nhacohen@mgh.harvard.edu.
¹⁸ Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA. Electronic address: msade-feldman@mgh.harvard.edu.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

COVID-19*
Humans
Immunoglobulin A
Immunoglobulin G
Neutrophils
Phenotype
SARS-CoV-2

Substances

Immunoglobulin A
Immunoglobulin G

Abstract

Publication types

MeSH terms

Substances

Grants and funding