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.
Author list:
Affiliations
- 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
- Cambridge Institute for Medical Research, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus, Cambridge
- Cellular Genetics, Wellcome Sanger Institute, Hinxton. United Kingdom
- Cancer Research UK - Cambridge Institute, Robinson Way, Cambridge CB2 0RE, United Kingdom
- EMBL-EBI, Wellcome Genome Campus, Hinxton, United Kingdom
- Department of Haematology, Wellcome & MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, United Kingdom
- Heart and Lung Research Institute, Cambridge Biomedical Campus, Cambridge CB2 0QQ, United Kingdom
- NIHR BioResource, Cambridge University Hospitals NHS Foundation, Cambridge Biomedical Campus, Cambridge CB2 0QQ, United Kingdom
Authors
Prasanti Kotagiri1,2 Federica Mescia1,2 Aimee L. Hanson1,2 Lorinda Turner1,2 Laura Bergamaschi1,2 Ana Peñalver3 Nathan Richoz1,2,4 Stephen D. Moore2 Brian M. Ortmann1,2 Benjamin J. Dunmore2 Michael D. Morgan5,6 Zewen Kelvin Tuong1,2,4 Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) COVID BioResource Collaboration, Berthold Göttgens7 Mark Toshner2,8 Christoph Hess1,2 Patrick. H. Maxwell2,3 Menna. R. Clatworthy1,2,4 James A. Nathan1,2 John R. Bradley2,9 Paul A. Lyons1,2 Natalie Burrows2,3* and Kenneth G.C. Smith1,2*
