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

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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

Bibliographical note

We thank the patients and Health Care Workers who took part in this study. We are grateful for financial support from CVC Capital Partners, the Evelyn Trust (20/75), Addenbrooke’s Charitable Trust (12/20A) and the UKRI/NIHR through the UK Coronavirus Immunology Consortium (UK-CIC). We acknowledge NIHR Cambridge BioResource Centre (Grant codes:RG85445 and RG94028), NIHR Cambridge Clinic Research Facility outreach team, relevant NHS Trusts and their staff, and the Wellcome Trust (no. 19710) for supporting murine studies. K.G.C.S. is the recipient of a Wellcome Investigator Award (200871/Z/16/Z); C.H. was funded by a Wellcome COVID-19 Rapid Response DCF and the Fondation Botnar. J.A.N is the recipient of a Wellcome Senior Clinical Research Fellowship (215477/Z/19/Z) and a Lister Institute Research Fellowship. NB and AP are supported by the Wellcome Trust, Senior Investigator Award to P.H.M, and the Rosetrees Trust. NR is supported by the NIHR Cambridge Biomedical Research Centre. Z.K.T. and M.R.C. are supported by a Medical Research Council Human Cell Atlas Research Grant (MR/S035842/1). M.R.C is supported by an NIHR Research Professorship (RP-2017-08-ST2-002). PK is the recipient of a Jacquot Research Entry Scholarship of the Royal Australasian College of Physicians Foundation. We thank the NIHR, NHS Blood and Transplant, and Health Data Research UK as part of the Digital Innovation Hub Programme, and the NIHR Cambridge Biomedical Research Centre Cell Phenotyping Hub, the CRUK Cambridge Institute cytometry core and the Cambridge NIHR BRC Stratified Medicine Core Laboratory NGS Hub.

Data Availability Statement

Data sharing statement
The dataset from our study can be explored interactively through a web portal:

Supplementary materials
Supplementary material associated with this article can be found in the online version at doi:10.1016/j.ebiom.2022.103878.


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


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