The impact of hypoxia on B cells in COVID-19

Prasanti Kotagiri, Federica Mescia, Aimee L Hanson, Lorinda Turner, Laura Bergamaschi, Ana Peñalver, Nathan Richoz, Stephen D Moore, Brian M Ortmann, Benjamin J Dunmore, Michael D Morgan, Zewen Kelvin Tuong, Berthold Göttgens, Mark Toshner, Christoph Hess, Patrick H Maxwell, Menna R Clatworthy, James A Nathan, John R Bradley, Paul A LyonsNatalie Burrows* (Corresponding Author), Kenneth G C Smith* (Corresponding Author), Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) Covid BioResource Collaboration

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article number103878
Early online date19 Feb 2022
Publication statusPublished - 1 Mar 2022


  • Animals
  • COVID-19
  • Humans
  • Hypoxia
  • Mice
  • Oxygen
  • Pneumonia
  • SARS-CoV-2
  • B cells
  • Lymphopenia


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