Multi-omic profiling reveals widespread dysregulation of innate immunity and hematopoiesis in COVID-19.
Aaron J Wilk, Madeline J Lee, Bei Wei, Benjamin Parks, Ruoxi Pi, Giovanny J Martínez-Colón, Thanmayi Ranganath, Nancy Q Zhao, Shalina Taylor, Winston Becker, Stanford COVID-19 Biobank, David Jimenez-Morales, Andra L Blomkalns, Ruth O'Hara, Euan A Ashley, Kari C Nadeau, Samuel Yang, Susan Holmes, Marlene Rabinovitch, Angela J Rogers, William J Greenleaf, Catherine A Blish
Author Information
Aaron J Wilk: Stanford Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA. ORCID
Madeline J Lee: Stanford Immunology Program, Stanford University School of Medicine, Stanford, CA. ORCID
Bei Wei: Department of Genetics, Stanford University School of Medicine, Stanford, CA. ORCID
Benjamin Parks: Department of Genetics, Stanford University School of Medicine, Stanford, CA. ORCID
Ruoxi Pi: Department of Medicine, Stanford University School of Medicine, Stanford, CA. ORCID
Giovanny J Martínez-Colón: Department of Medicine, Stanford University School of Medicine, Stanford, CA. ORCID
Thanmayi Ranganath: Department of Medicine, Stanford University School of Medicine, Stanford, CA. ORCID
Nancy Q Zhao: Department of Medicine, Stanford University School of Medicine, Stanford, CA. ORCID
Shalina Taylor: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA. ORCID
Winston Becker: Department of Genetics, Stanford University School of Medicine, Stanford, CA. ORCID
David Jimenez-Morales: Department of Medicine, Stanford University School of Medicine, Stanford, CA. ORCID
Andra L Blomkalns: Department of Emergency Medicine, Stanford University School of Medicine, Stanford, CA. ORCID
Ruth O'Hara: Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA. ORCID
Euan A Ashley: Department of Medicine, Stanford University School of Medicine, Stanford, CA. ORCID
Kari C Nadeau: Department of Medicine, Stanford University School of Medicine, Stanford, CA. ORCID
Samuel Yang: Department of Emergency Medicine, Stanford University School of Medicine, Stanford, CA. ORCID
Susan Holmes: Department of Statistics, Stanford University, Stanford, CA. ORCID
Marlene Rabinovitch: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA. ORCID
Angela J Rogers: Department of Medicine, Stanford University School of Medicine, Stanford, CA. ORCID
William J Greenleaf: Department of Genetics, Stanford University School of Medicine, Stanford, CA. ORCID
Catherine A Blish: Stanford Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA. ORCID
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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