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; Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) Covid BioResource Collaboration

doi:10.1016/j.ebiom.2022.103878

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

Medical Sciences

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	103878
Journal	EBioMedicine
Volume	77
Early online date	19 Feb 2022
DOIs	https://doi.org/10.1016/j.ebiom.2022.103878
Publication status	Published - 1 Mar 2022

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Kotagiri, P., Mescia, F., Hanson, A. L., Turner, L., Bergamaschi, L., Peñalver, A., Richoz, N., Moore, S. D., Ortmann, B. M., Dunmore, B. J., Morgan, M. D., Tuong, Z. K., Göttgens, B., Toshner, M., Hess, C., Maxwell, P. H., Clatworthy, M. R., Nathan, J. A., Bradley, J. R., ... Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) Covid BioResource Collaboration (2022). The impact of hypoxia on B cells in COVID-19. EBioMedicine, 77, [103878]. https://doi.org/10.1016/j.ebiom.2022.103878

Kotagiri, P, Mescia, F, Hanson, AL, Turner, L, Bergamaschi, L, Peñalver, A, Richoz, N, Moore, SD, Ortmann, BM, Dunmore, BJ, Morgan, MD, Tuong, ZK, Göttgens, B, Toshner, M, Hess, C, Maxwell, PH, Clatworthy, MR, Nathan, JA, Bradley, JR, Lyons, PA, Burrows, N, Smith, KGC & Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) Covid BioResource Collaboration 2022, 'The impact of hypoxia on B cells in COVID-19', EBioMedicine, vol. 77, 103878. https://doi.org/10.1016/j.ebiom.2022.103878

@article{89b25475010943f4870e6ea305e2303c,

title = "The impact of hypoxia on B cells in COVID-19",

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.",

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

author = "Prasanti Kotagiri and Federica Mescia and Hanson, {Aimee L} and Lorinda Turner and Laura Bergamaschi and Ana Pe{\~n}alver and Nathan Richoz and Moore, {Stephen D} and Ortmann, {Brian M} and Dunmore, {Benjamin J} and Morgan, {Michael D} and Tuong, {Zewen Kelvin} and Berthold G{\"o}ttgens and Mark Toshner and Christoph Hess and Maxwell, {Patrick H} and Clatworthy, {Menna R} and Nathan, {James A} and Bradley, {John R} and Lyons, {Paul A} and Natalie Burrows and Smith, {Kenneth G C} and {Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) Covid BioResource Collaboration}",

note = "Acknowledgements 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{\textquoteright}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.",

year = "2022",

month = mar,

day = "1",

doi = "10.1016/j.ebiom.2022.103878",

language = "English",

volume = "77",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier BV",

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TY - JOUR

T1 - The impact of hypoxia on B cells in COVID-19

AU - Kotagiri, Prasanti

AU - Mescia, Federica

AU - Hanson, Aimee L

AU - Turner, Lorinda

AU - Bergamaschi, Laura

AU - Peñalver, Ana

AU - Richoz, Nathan

AU - Moore, Stephen D

AU - Ortmann, Brian M

AU - Dunmore, Benjamin J

AU - Morgan, Michael D

AU - Tuong, Zewen Kelvin

AU - Göttgens, Berthold

AU - Toshner, Mark

AU - Hess, Christoph

AU - Maxwell, Patrick H

AU - Clatworthy, Menna R

AU - Nathan, James A

AU - Bradley, John R

AU - Lyons, Paul A

AU - Burrows, Natalie

AU - Smith, Kenneth G C

AU - Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) Covid BioResource Collaboration

N1 - Acknowledgements 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.

PY - 2022/3/1

Y1 - 2022/3/1

N2 - 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.

AB - 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.

KW - Animals

KW - COVID-19

KW - Humans

KW - Hypoxia

KW - Mice

KW - Oxygen

KW - Pneumonia

KW - SARS-CoV-2

KW - B cells

KW - Lymphopenia

U2 - 10.1016/j.ebiom.2022.103878

DO - 10.1016/j.ebiom.2022.103878

M3 - Article

C2 - 35189575

VL - 77

JO - EBioMedicine

JF - EBioMedicine

SN - 2352-3964

M1 - 103878

ER -

The impact of hypoxia on B cells in COVID-19

Abstract

Keywords

UN SDGs

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