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The impact of hypoxia on B cells in COVID-19.
Kotagiri, Prasanti; Mescia, Federica; Hanson, Aimee L; Turner, Lorinda; Bergamaschi, Laura; Peñalver, Ana; Richoz, Nathan; Moore, Stephen D; Ortmann, Brian M; Dunmore, Benjamin J; Morgan, Michael D; Tuong, Zewen Kelvin; Göttgens, Berthold; Toshner, Mark; Hess, Christoph; Maxwell, Patrick H; Clatworthy, Menna R; Nathan, James A; Bradley, John R; Lyons, Paul A; Burrows, Natalie; Smith, Kenneth G C.
  • Kotagiri P; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, United Kingdom; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom.
  • Mescia F; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, United Kingdom; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom.
  • Hanson AL; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, United Kingdom; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom.
  • Turner L; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, United Kingdom; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom.
  • Bergamaschi L; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, United Kingdom; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom.
  • Peñalver A; Cambridge Institute for Medical Research, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus, Cambridge.
  • Richoz N; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, United Kingdom; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom; Cellular Genetics, Wellco
  • Moore SD; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom.
  • Ortmann BM; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, United Kingdom; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom.
  • Dunmore BJ; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom.
  • Morgan MD; Cancer Research UK - Cambridge Institute, Robinson Way, Cambridge CB2 0RE, United Kingdom; EMBL-EBI, Wellcome Genome Campus, Hinxton, United Kingdom.
  • Tuong ZK; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, United Kingdom; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom; Cellular Genetics, Wellco
  • Göttgens B; Department of Haematology, Wellcome & MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, United Kingdom.
  • Toshner M; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom; Heart and Lung Research Institute, Cambridge Biomedical Campus, Cambridge CB2 0QQ, United Kingdom.
  • Hess C; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, United Kingdom; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom.
  • Maxwell PH; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom; Cambridge Institute for Medical Research, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus, Cambridge.
  • Clatworthy MR; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, United Kingdom; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom; Cellular Genetics, Wellco
  • Nathan JA; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, United Kingdom; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom.
  • Bradley JR; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom; NIHR BioResource, Cambridge University Hospitals NHS Foundation, Cambridge Biomedical Campus, Cambridge CB2 0QQ, United Kingdom.
  • Lyons PA; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, United Kingdom; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom.
  • Burrows N; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom; Cambridge Institute for Medical Research, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus, Cambridge. Electronic address: nb470@cam.ac.uk.
  • Smith KGC; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, United Kingdom; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom. Electronic address: kgcs2
EBioMedicine ; 77: 103878, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1693688
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Pneumonia / COVID-19 Limits: Animals / Humans Language: English Journal: EBioMedicine Year: 2022 Document Type: Article Affiliation country: J.ebiom.2022.103878

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Pneumonia / COVID-19 Limits: Animals / Humans Language: English Journal: EBioMedicine Year: 2022 Document Type: Article Affiliation country: J.ebiom.2022.103878