Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 218, Issue 8, Pages -Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20210582
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Funding
- National Heart, Lung, and Blood Institute [K23 HL125663]
- Stanford Medical Scientist Training Program [T32 GM007365-44]
- Stanford Bio-X Interdisciplinary Graduate Fellowship
- Wallenberg Foundation Post-Doctoral Fellowship
- National Institute of Standards and Technology
- National Institute on Drug Abuse [DP1 (DP1 DA046089)]
- Bill and Melinda Gates Foundation
- Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Diseases [1016687]
- Tashia and John Morgridge Faculty Scholar in Pediatric Translational Medicine from the Stanford Maternal ChildHealth Research Institute
- Defense Advanced Research Projects Agency
- National Institutes of Health
- Chan-Zuckerberg Initiative
- Rita Allen Foundation
- Stanford University Interdisciplinary Graduate Fellowship
- NIH
- Personalis, Inc.
- SVEXA Inc.
- Astra Zeneca
- Gilead
- Genome Medical
- National Institute of Allergy and Infectious Diseases, National Heart, Lung, and Blood Institute, Food Allergy Research and Education
- World Allergy Organization
- Before Brands
- Guardant Health
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The study revealed immune system dysfunctions in COVID-19 patients at different disease severity stages, particularly in severe and fatal cases. It also found a lack of pro-inflammatory cytokine production in severe cases, potentially due to chromatin accessibility changes as a mechanism.
Our understanding of protective versus pathological immune responses to SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), is limited by inadequate profiling of patients at the extremes of the disease severity spectrum. Here, we performed multi-omic single-cell immune profiling of 64 COVID-19 patients across the full range of disease severity, from outpatients with mild disease to fatal cases. Our transcriptomic, epigenomic, and proteomic analyses revealed widespread dysfunction of peripheral innate immunity in severe and fatal COVID-19, including prominent hyperactivation signatures in neutrophils and NK cells. We also identified chromatin accessibility changes at NF-kappa B binding sites within cytokine gene loci as a potential mechanism for the striking lack of pro-inflammatory cytokine production observed in monocytes in severe and fatal COVID-19. We further demonstrated that emergency myelopoiesis is a prominent feature of fatal COVID-19. Collectively, our results reveal disease severity-associated immune phenotypes in COVID-19 and identify pathogenesis-associated pathways that are potential targets for therapeutic intervention.
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