Multi-omic profiling reveals widespread dysregulation of innate immunity and hematopoiesis in COVID-19

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 o...

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Published inThe Journal of experimental medicine Vol. 218; no. 8
Main Authors Wilk, Aaron J., Lee, Madeline J., Wei, Bei, Parks, Benjamin, Pi, Ruoxi, Martínez-Colón, Giovanny J., Ranganath, Thanmayi, Zhao, Nancy Q., Taylor, Shalina, Becker, Winston, Vergara, Rosemary, McKechnie, Julia L., de la Parte, Lauren, Whittle Dantzler, Kathleen, Ty, Maureen, Kathale, Nimish, Martinez-Colon, Giovanny J., Rustagi, Arjun, Ivison, Geoff, Brewer, Rachel, Hollis, Taylor, Baird, Andrea, Ugur, Michele, Tal, Michal, Bogusch, Drina, Nahass, Georgie, Haider, Kazim, Thi Tran, Kim Quyen, Simpson, Laura, Din, Hena, Roque, Jonasel, Mann, Rosen, Chang, Iris, Do, Evan, Fernandes, Andrea, Lyu, Shu-Chen, Zhang, Wenming, Manohar, Monali, Krempski, James, Visweswaran, Anita, Zudock, Elizabeth J., Jee, Kathryn, Kumar, Komal, Newberry, Jennifer A., Quinn, James V., Schreiber, Donald, Ashley, Euan A., Blish, Catherine A., Blomkalns, Andra L., Nadeau, Kari C., O’Hara, Ruth, Rogers, Angela J., Yang, Samuel, Jimenez-Morales, David, Holmes, Susan, Rabinovitch, Marlene, Greenleaf, William J.
Format Journal Article
LanguageEnglish
Published United States Rockefeller University Press 02.08.2021
Subjects
Adult
Aged
Case-Control Studies
Covid-19
COVID-19 - blood
COVID-19 - genetics
COVID-19 - immunology
COVID-19 - mortality
Cytokines - genetics
Epigenesis, Genetic
Female
Hematopoiesis
Humans
Immunity, Innate - physiology
Infectious Disease and Host Defense
Innate Immunity and Inflammation
Killer Cells, Natural - pathology
Killer Cells, Natural - virology
Male
Middle Aged
Monocytes - pathology
Monocytes - virology
Neutrophils - pathology
Neutrophils - virology
NF-kappa B - metabolism
Proteomics
Severity of Illness Index
Single-Cell Analysis
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Summary: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-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. 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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Disclosures: A.J. Wilk reported grants from Stanford University Interdisciplinary Graduate Fellowship and NIH during the conduct of the study. M.J. Lee reported grants from NIH during the conduct of the study. B. Wei reported "Stanford University." E.A. 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. K.C. 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. 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. A.J. Rogers reported personal fees from Merck outside the submitted work. W.J. 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. Greenleaf had a patent to US20160060691A1 with royalties paid (10x Genomics). C.A. Blish reported personal fees from Catamaran Bio outside the submitted work. No other disclosures were reported.
A.J. Wilk, M.J. Lee, B. Wei, and B. Parks contributed equally to this paper.
Stanford COVID-19 Biobank members: Thanmayi Ranganath, Nancy Q. Zhao, Aaron J. Wilk, Rosemary Vergara, Julia L. McKechnie, Lauren de la Parte, Kathleen Whittle Dantzler, Maureen Ty, Nimish Kathale, Giovanny J. Martínez-Colón, Arjun Rustagi, Geoff Ivison, Ruoxi Pi, Madeline J. Lee, Rachel Brewer, Taylor Hollis, Andrea Baird, Michele Ugur, Michal Tal, Drina Bogusch, Georgie Nahass, Kazim Haider, Kim Quyen Thi Tran, Laura Simpson, Hena Din, Jonasel Roque, Rosen Mann, Iris Chang, Evan Do, Andrea Fernandes, Shu-Chen Lyu, Wenming Zhang, Monali Manohar, James Krempski, Anita Visweswaran, Elizabeth J. Zudock, Kathryn Jee, Komal Kumar, Jennifer A. Newberry, James V. Quinn, Donald Schreiber, Euan A. Ashley, Catherine A. Blish, Andra L. Blomkalns, Kari C. Nadeau, Ruth O’Hara, Angela J. Rogers, Samuel Yang.
ISSN:0022-1007
1540-9538
1540-9538
DOI:10.1084/jem.20210582