Coagulation factor V is a T-cell inhibitor expressed by leukocytes in COVID-19

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

doi:10.1016/j.isci.2022.103971

Coagulation factor V is a T-cell inhibitor expressed by leukocytes in COVID-19

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

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

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Abstract

Clotting Factor V (FV) is primarily synthesized in the liver and when cleaved by thrombin forms pro-coagulant Factor Va (FVa). Using whole blood RNAseq and scRNAseq of peripheral blood mononuclear cells, we find that FV mRNA is expressed in leukocytes, and identify neutrophils, monocytes, and T regulatory cells as sources of increased FV in hospitalized patients with COVID-19. Proteomic analysis confirms increased FV in circulating neutrophils in severe COVID-19, and immunofluorescence microscopy identifies FV in lung-infiltrating leukocytes in COVID-19 lung disease. Increased leukocyte FV expression in severe disease correlates with T-cell lymphopenia. Both plasma-derived and a cleavage resistant recombinant FV, but not thrombin cleaved FVa, suppress T-cell proliferation in vitro. Anticoagulants that reduce FV conversion to FVa, including heparin, may have the unintended consequence of suppressing the adaptive immune system.

Original language	English
Pages (from-to)	103971
Journal	iScience
Volume	25
Issue number	3
Early online date	8 Mar 2022
DOIs	https://doi.org/10.1016/j.isci.2022.103971
Publication status	Published - 18 Mar 2022

Bibliographical note

This work was supported by the NIHR BioResource, the NIHR Cambridge Biomedical Research Centre and the NIHR Cambridge Clinical Research Facility. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. We thank NIHR BioResource volunteers for their participation, and gratefully acknowledge NIHR BioResource centres, NHS Trusts and staff for their contribution. FV plasma assays were performed by the NIHR Cambridge Biochemical Assay Laboratory. The Cambridge University Hospitals Research Tissue Bank is supported by the NIHR Cambridge Biomedical Research Centre. FV constructs were prepared and expressed by Peak Proteins. Neutrophil proteins were characterized at the Mass Spectrometry Facility at the University of Dundee and the QMRI flow cytometry and cell sorting facility. Sequencing was supported by Paul Coupland from the CRUK Cambridge Institute Genomics Core. The graphical abstract was produced using Biorender (https://biorender.com/). The work was funded by awards from NIHR to the NIHR BioResource and the NIHR Cambridge Biomedical Research Centre, Evelyn Trust, Addenbrooke's Charitable Trust, UKRI/NIHR funding through the UK Coronavirus Immunology Consortium (UK-CIC) and a CSO award (COV/DUN/20/01). KGCS holds a Wellcome Trust Investigator award. BG holds an award from the Aging Biology Foundation Europe to BG. RKG holds a Wellcome Senior Fellowship (WT108082AIA). PK is supported by the Australian and New Zealand Society of Nephrology and the Royal Australasian College of Physicians. SRW holds a Wellcome Trust Senior Clinical Fellowship (209220). ERW holds a Wellcome Clinical Training Fellowship award (108717/Z/15/Z). NM was supported by a DFG Research Fellowship. PFC is a Wellcome Trust Principal Research Fellow (212219/Z/18/Z), and a NIHR Senior Investigator, and receives support from the Medical Research Council (MRC) Mitochondrial Biology Unit, the MRC International Centre for Genomic Medicine in Neuromuscular Disease, the Leverhulme Trust, an MRC research grant, and an Alzheimer's Society Project Grant. JAN holds a Wellcome Trust Senior Research Fellowship (215477/Z/19/Z).

Data Availability Statement

Data and code availability
•
scRNAseqdata is available through ArrayExpress. The DOI is listed in the key resources table. Whole blood RNAseq is available at the European Genome Archive. The DOI is listed in the key resources table.

•
De-identified human/patient data are publicly available as of the date of publication. DOI and accession numbers are listed in the key resources table.

•
This paper does not report original code.

•
Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

Keywords

Immunology
Microbiology
Omics
Transcriptomics

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10.1016/j.isci.2022.103971Licence: CC BY

Wang_etal_IS_Coagulation_Factor_V_VOR
iScience 25, 103971, March 18, 2022 ª 2022 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Final published version, 3.07 MBLicence: CC BY

Cite this

@article{fc5028b7958a4563963eb4264170528b,

title = "Coagulation factor V is a T-cell inhibitor expressed by leukocytes in COVID-19",

abstract = "Clotting Factor V (FV) is primarily synthesized in the liver and when cleaved by thrombin forms pro-coagulant Factor Va (FVa). Using whole blood RNAseq and scRNAseq of peripheral blood mononuclear cells, we find that FV mRNA is expressed in leukocytes, and identify neutrophils, monocytes, and T regulatory cells as sources of increased FV in hospitalized patients with COVID-19. Proteomic analysis confirms increased FV in circulating neutrophils in severe COVID-19, and immunofluorescence microscopy identifies FV in lung-infiltrating leukocytes in COVID-19 lung disease. Increased leukocyte FV expression in severe disease correlates with T-cell lymphopenia. Both plasma-derived and a cleavage resistant recombinant FV, but not thrombin cleaved FVa, suppress T-cell proliferation in vitro. Anticoagulants that reduce FV conversion to FVa, including heparin, may have the unintended consequence of suppressing the adaptive immune system.",

keywords = "Immunology, Microbiology, Omics, Transcriptomics",

author = "Jun Wang and Prasanti Kotagiri and Lyons, {Paul A} and Al-Lamki, {Rafia S} and Federica Mescia and Laura Bergamaschi and Lorinda Turner and Morgan, {Michael D} and Calero-Nieto, {Fernando J} and Karsten Bach and Nicole Mende and Wilson, {Nicola K} and Watts, {Emily R} and Maxwell, {Patrick H} and Chinnery, {Patrick F} and Nathalie Kingston and Sofia Papadia and Stirrups, {Kathleen E} and Neil Walker and Gupta, {Ravindra K} and Menon, {David K} and Kieren Allinson and Aitken, {Sarah J} and Mark Toshner and Weekes, {Michael P} and Nathan, {James A} and Walmsley, {Sarah R} and Ouwehand, {Willem H} and Mary Kasanicki and Berthold G{\"o}ttgens and Marioni, {John C} and Smith, {Kenneth G C} and Pober, {Jordan S} and Bradley, {John R} and {Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) Covid BioResource Collaboration}",

note = "This work was supported by the NIHR BioResource, the NIHR Cambridge Biomedical Research Centre and the NIHR Cambridge Clinical Research Facility. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. We thank NIHR BioResource volunteers for their participation, and gratefully acknowledge NIHR BioResource centres, NHS Trusts and staff for their contribution. FV plasma assays were performed by the NIHR Cambridge Biochemical Assay Laboratory. The Cambridge University Hospitals Research Tissue Bank is supported by the NIHR Cambridge Biomedical Research Centre. FV constructs were prepared and expressed by Peak Proteins. Neutrophil proteins were characterized at the Mass Spectrometry Facility at the University of Dundee and the QMRI flow cytometry and cell sorting facility. Sequencing was supported by Paul Coupland from the CRUK Cambridge Institute Genomics Core. The graphical abstract was produced using Biorender (https://biorender.com/). The work was funded by awards from NIHR to the NIHR BioResource and the NIHR Cambridge Biomedical Research Centre, Evelyn Trust, Addenbrooke's Charitable Trust, UKRI/NIHR funding through the UK Coronavirus Immunology Consortium (UK-CIC) and a CSO award (COV/DUN/20/01). KGCS holds a Wellcome Trust Investigator award. BG holds an award from the Aging Biology Foundation Europe to BG. RKG holds a Wellcome Senior Fellowship (WT108082AIA). PK is supported by the Australian and New Zealand Society of Nephrology and the Royal Australasian College of Physicians. SRW holds a Wellcome Trust Senior Clinical Fellowship (209220). ERW holds a Wellcome Clinical Training Fellowship award (108717/Z/15/Z). NM was supported by a DFG Research Fellowship. PFC is a Wellcome Trust Principal Research Fellow (212219/Z/18/Z), and a NIHR Senior Investigator, and receives support from the Medical Research Council (MRC) Mitochondrial Biology Unit, the MRC International Centre for Genomic Medicine in Neuromuscular Disease, the Leverhulme Trust, an MRC research grant, and an Alzheimer's Society Project Grant. JAN holds a Wellcome Trust Senior Research Fellowship (215477/Z/19/Z).",

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T1 - Coagulation factor V is a T-cell inhibitor expressed by leukocytes in COVID-19

AU - Wang, Jun

AU - Kotagiri, Prasanti

AU - Lyons, Paul A

AU - Al-Lamki, Rafia S

AU - Mescia, Federica

AU - Bergamaschi, Laura

AU - Turner, Lorinda

AU - Morgan, Michael D

AU - Calero-Nieto, Fernando J

AU - Bach, Karsten

AU - Mende, Nicole

AU - Wilson, Nicola K

AU - Watts, Emily R

AU - Maxwell, Patrick H

AU - Chinnery, Patrick F

AU - Kingston, Nathalie

AU - Papadia, Sofia

AU - Stirrups, Kathleen E

AU - Walker, Neil

AU - Gupta, Ravindra K

AU - Menon, David K

AU - Allinson, Kieren

AU - Aitken, Sarah J

AU - Toshner, Mark

AU - Weekes, Michael P

AU - Nathan, James A

AU - Walmsley, Sarah R

AU - Ouwehand, Willem H

AU - Kasanicki, Mary

AU - Göttgens, Berthold

AU - Marioni, John C

AU - Smith, Kenneth G C

AU - Pober, Jordan S

AU - Bradley, John R

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

N1 - This work was supported by the NIHR BioResource, the NIHR Cambridge Biomedical Research Centre and the NIHR Cambridge Clinical Research Facility. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. We thank NIHR BioResource volunteers for their participation, and gratefully acknowledge NIHR BioResource centres, NHS Trusts and staff for their contribution. FV plasma assays were performed by the NIHR Cambridge Biochemical Assay Laboratory. The Cambridge University Hospitals Research Tissue Bank is supported by the NIHR Cambridge Biomedical Research Centre. FV constructs were prepared and expressed by Peak Proteins. Neutrophil proteins were characterized at the Mass Spectrometry Facility at the University of Dundee and the QMRI flow cytometry and cell sorting facility. Sequencing was supported by Paul Coupland from the CRUK Cambridge Institute Genomics Core. The graphical abstract was produced using Biorender (https://biorender.com/). The work was funded by awards from NIHR to the NIHR BioResource and the NIHR Cambridge Biomedical Research Centre, Evelyn Trust, Addenbrooke's Charitable Trust, UKRI/NIHR funding through the UK Coronavirus Immunology Consortium (UK-CIC) and a CSO award (COV/DUN/20/01). KGCS holds a Wellcome Trust Investigator award. BG holds an award from the Aging Biology Foundation Europe to BG. RKG holds a Wellcome Senior Fellowship (WT108082AIA). PK is supported by the Australian and New Zealand Society of Nephrology and the Royal Australasian College of Physicians. SRW holds a Wellcome Trust Senior Clinical Fellowship (209220). ERW holds a Wellcome Clinical Training Fellowship award (108717/Z/15/Z). NM was supported by a DFG Research Fellowship. PFC is a Wellcome Trust Principal Research Fellow (212219/Z/18/Z), and a NIHR Senior Investigator, and receives support from the Medical Research Council (MRC) Mitochondrial Biology Unit, the MRC International Centre for Genomic Medicine in Neuromuscular Disease, the Leverhulme Trust, an MRC research grant, and an Alzheimer's Society Project Grant. JAN holds a Wellcome Trust Senior Research Fellowship (215477/Z/19/Z).

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Y1 - 2022/3/18

N2 - Clotting Factor V (FV) is primarily synthesized in the liver and when cleaved by thrombin forms pro-coagulant Factor Va (FVa). Using whole blood RNAseq and scRNAseq of peripheral blood mononuclear cells, we find that FV mRNA is expressed in leukocytes, and identify neutrophils, monocytes, and T regulatory cells as sources of increased FV in hospitalized patients with COVID-19. Proteomic analysis confirms increased FV in circulating neutrophils in severe COVID-19, and immunofluorescence microscopy identifies FV in lung-infiltrating leukocytes in COVID-19 lung disease. Increased leukocyte FV expression in severe disease correlates with T-cell lymphopenia. Both plasma-derived and a cleavage resistant recombinant FV, but not thrombin cleaved FVa, suppress T-cell proliferation in vitro. Anticoagulants that reduce FV conversion to FVa, including heparin, may have the unintended consequence of suppressing the adaptive immune system.

AB - Clotting Factor V (FV) is primarily synthesized in the liver and when cleaved by thrombin forms pro-coagulant Factor Va (FVa). Using whole blood RNAseq and scRNAseq of peripheral blood mononuclear cells, we find that FV mRNA is expressed in leukocytes, and identify neutrophils, monocytes, and T regulatory cells as sources of increased FV in hospitalized patients with COVID-19. Proteomic analysis confirms increased FV in circulating neutrophils in severe COVID-19, and immunofluorescence microscopy identifies FV in lung-infiltrating leukocytes in COVID-19 lung disease. Increased leukocyte FV expression in severe disease correlates with T-cell lymphopenia. Both plasma-derived and a cleavage resistant recombinant FV, but not thrombin cleaved FVa, suppress T-cell proliferation in vitro. Anticoagulants that reduce FV conversion to FVa, including heparin, may have the unintended consequence of suppressing the adaptive immune system.

KW - Immunology

KW - Microbiology

KW - Omics

KW - Transcriptomics

U2 - 10.1016/j.isci.2022.103971

DO - 10.1016/j.isci.2022.103971

M3 - Article

C2 - 35224470

VL - 25

SP - 103971

JO - iScience

JF - iScience

IS - 3

ER -

Coagulation factor V is a T-cell inhibitor expressed by leukocytes in COVID-19

Abstract

Bibliographical note

Data Availability Statement

Keywords

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Cite this