1. The impact of hypoxia on B cells in COVID-19
- Author
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Kotagiri, P, Mescia, F, Hanson, AL, Turner, L, Bergamaschi, L, Penalver, A, Richoz, N, Moore, SD, Ortmann, BM, Dunmore, BJ, Morgan, MD, Tuong, ZK, Gottgens, B, Toshner, M, Hess, C, Maxwell, PH, Clatworthy, MR, Nathan, JA, Bradley, JR, Lyons, PA, Burrows, N, Smith, KGC, Kotagiri, P, Mescia, F, Hanson, AL, Turner, L, Bergamaschi, L, Penalver, A, Richoz, N, Moore, SD, Ortmann, BM, Dunmore, BJ, Morgan, MD, Tuong, ZK, Gottgens, B, Toshner, M, Hess, C, Maxwell, PH, Clatworthy, MR, Nathan, JA, Bradley, JR, Lyons, PA, Burrows, N, and Smith, KGC
- 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.
- Published
- 2022