Severe COVID-19 is associated with a number of distinct immunological signatures. Collectively, our results reveal disease severity–associated immune phenotypes in COVID-19 and identify pathogenesis-associated pathways that are potential targets for therapeutic intervention. We further demonstrated that emergency myelopoiesis is a prominent feature of fatal COVID-19. We also identified chromatin accessibility changes at NF-κB 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. 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. 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 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. Blish reported personal fees from Catamaran Bio outside the submitted work. Greenleaf had a patent to US20160060691A1 with royalties paid (10x Genomics).
Greenleaf reported personal fees from 10x Genomics during the conduct of the study, and personal fees from Guardant Health and Protillion Biosciences outside the submitted work in addition, W.J. Rogers reported personal fees from Merck outside the submitted work. Nadeau had a patent to "mixed allergen composition and methods for using the same with royalties paid (Alladapt and Before Brands), a patent to "granulocyte-based methods for detecting and monitoring immune system disorders" issued, and a patent to "methods and assays for detecting and quantifying pure subpopulations of white blood cells in immune system disorders" issued. Nadeau reported grants from National Institute of Allergy and Infectious Diseases, National Heart, Lung, and Blood Institute, Food Allergy Research and Education, and World Allergy Organization "other" from Cour Pharma, Before Brands, Alladapt, Latitude, IgGenix, Immune Tolerance Network, and National Institutes of Health clinical research centers outside the submitted work in addition, K.C. Ashley reported "other" from Personalis, Inc., DeepCell, Inc., SVEXA Inc., Astra Zeneca, Gilead, MyoKardia, Amgen, Takeda, Novartis, Genome Medical, Avive, Samsung, Apple Inc., Google, Verily, Disney Inc., Illumina Inc., PacBio, Nanopore, Foresite Capital, and Sequence Bio outside the submitted work. Lee reported grants from NIH during the conduct of the study. Wilk reported grants from Stanford University Interdisciplinary Graduate Fellowship and NIH during the conduct of the study.
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