EBioMedicine (Mar 2022)

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. Lyons,
  • Natalie Burrows,
  • Kenneth G.C. Smith

Journal volume & issue
Vol. 77
p. 103878

Abstract

Read online

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

Keywords