Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, United Kingdom; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom
Federica Mescia
Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, United Kingdom; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom
Aimee L. Hanson
Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, United Kingdom; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom
Lorinda Turner
Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, United Kingdom; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom
Laura Bergamaschi
Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, United Kingdom; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom
Ana Peñalver
Cambridge Institute for Medical Research, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus, Cambridge
Nathan Richoz
Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, United Kingdom; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom; Cellular Genetics, Wellcome Sanger Institute, Hinxton. United Kingdom
Stephen D. Moore
Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom
Brian M. Ortmann
Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, United Kingdom; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom
Benjamin J. Dunmore
Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom
Michael D. Morgan
Cancer Research UK – Cambridge Institute, Robinson Way, Cambridge CB2 0RE, United Kingdom; EMBL-EBI, Wellcome Genome Campus, Hinxton, United Kingdom
Zewen Kelvin Tuong
Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, United Kingdom; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom; Cellular Genetics, Wellcome Sanger Institute, Hinxton. United Kingdom
Berthold Göttgens
Department of Haematology, Wellcome & MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, United Kingdom
Mark Toshner
Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom; Heart and Lung Research Institute, Cambridge Biomedical Campus, Cambridge CB2 0QQ, United Kingdom
Christoph Hess
Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, United Kingdom; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom
Patrick. H. Maxwell
Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom; Cambridge Institute for Medical Research, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus, Cambridge
Menna. R. Clatworthy
Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, United Kingdom; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom; Cellular Genetics, Wellcome Sanger Institute, Hinxton. United Kingdom
James A. Nathan
Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, United Kingdom; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom
John R. Bradley
Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom; NIHR BioResource, Cambridge University Hospitals NHS Foundation, Cambridge Biomedical Campus, Cambridge CB2 0QQ, United Kingdom
Paul A. Lyons
Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, United Kingdom; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom
Natalie Burrows
Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom; Cambridge Institute for Medical Research, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus, Cambridge; Corresponding authors.
Kenneth G.C. Smith
Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, United Kingdom; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom; Corresponding authors.
Summary: Background: Prominent early features of COVID-19 include severe, often clinically silent, hypoxia and a pronounced reduction in B cells, the latter important in defence against SARS-CoV-2. This presentation resembles the phenotype of mice with VHL-deficient B cells, in which Hypoxia-Inducible Factors are constitutively active, suggesting hypoxia might drive B cell abnormalities in COVID-19. Methods: Detailed B cell phenotyping was undertaken by flow-cytometry on longitudinal samples from patients with COVID-19 across a range of severities (NIHR Cambridge BioResource). The impact of hypoxia on the transcriptome was assessed by single-cell and whole blood RNA sequencing analysis. The direct effect of hypoxia on B cells was determined through immunisation studies in genetically modified and hypoxia-exposed mice. Findings: We demonstrate the breadth of early and persistent defects in B cell subsets in moderate/severe COVID-19, including reduced marginal zone-like, memory and transitional B cells, changes also observed in B cell VHL-deficient mice. These findings were associated with hypoxia-related transcriptional changes in COVID-19 patient B cells, and similar B cell abnormalities were seen in mice kept in hypoxic conditions. Interpretation: Hypoxia may contribute to the pronounced and persistent B cell pathology observed in acute COVID-19 pneumonia. Assessment of the impact of early oxygen therapy on these immune defects should be considered, as their correction could contribute to improved outcomes. Funding: Evelyn Trust, Addenbrooke's Charitable Trust, UKRI/NIHR, Wellcome Trust