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The impact of hypoxia on B cells in COVID-19.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Kotagiri, Prasanti 
Mescia, Federica 
Hanson, Aimee L 
Turner, Lorinda 
Bergamaschi, Laura 

Abstract

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.

Description

Funder: Evelyn Trust


Funder: NHSBT


Funder: MRC


Funder: NIHR


Funder: Cambridge University Hospitals NHS Foundation Trust

Keywords

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

Journal Title

EBioMedicine

Conference Name

Journal ISSN

2352-3964
2352-3964

Volume Title

77

Publisher

Elsevier BV
Sponsorship
Lister Institute of Preventive Medicine (unknown)
Wellcome Trust (215477/Z/19/Z)
Medical Research Council (MR/S036113/1)
Nadace Aging Biology Foundation Europe (7042020)
MRC (MR/W014556/1)
Evelyn Trust (20/75)
Wellcome Trust (200871/Z/16/Z)
Medical Research Council (MR/S035842/1)
Department of Health (via National Institute for Health Research (NIHR)) (RP-2017-08-ST2-002)
Medical Research Council (G0900951)
Medical Research Council (MC_PC_17230)
MRC (via University of Birmingham) (MR/V028448/1)
Wellcome Trust (096956/Z/11/Z)
Medical Research Council (MR/W018861/1)
Wellcome Trust (207498/Z/17/Z)
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