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

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

doi:10.1016/j.isci.2022.103971

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

iScience. 2022 Mar 18;25(3):103971. doi: 10.1016/j.isci.2022.103971. Epub 2022 Feb 22.

Authors

Jun Wang¹, Prasanti Kotagiri^{1

2}, Paul A Lyons^{1

2}, Rafia S Al-Lamki^{1

3}, Federica Mescia^{1

2}, Laura Bergamaschi^{1

2}, Lorinda Turner^{1

2}, Michael D Morgan^{4

5}, Fernando J Calero-Nieto⁶, Karsten Bach^{4

7}, Nicole Mende⁶, Nicola K Wilson⁶, Emily R Watts⁸; Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) Covid BioResource Collaboration; Patrick H Maxwell¹, Patrick F Chinnery^{9

10

11}, Nathalie Kingston^{9

5}, Sofia Papadia^{9

12}, Kathleen E Stirrups^{9

5}, Neil Walker^{9

5}, Ravindra K Gupta^{1

2}, David K Menon¹⁰, Kieren Allinson¹³, Sarah J Aitken^{4

13

14

15}, Mark Toshner^{1

16}, Michael P Weekes¹, James A Nathan^{1

2}, Sarah R Walmsley⁸, Willem H Ouwehand^{6

9

17}, Mary Kasanicki³, Berthold Göttgens⁶, John C Marioni^{18

4

19}, Kenneth G C Smith^{1

2}, Jordan S Pober^{1

20}, John R Bradley^{1

3

9}

Affiliations

¹ Department of Medicine, University of Cambridge, Addenbrookes Hospital, Box 157, Hills Rd, Cambridge CB2 0QQ, UK.
² Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK.
³ Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
⁴ Cancer Research UK -Cambridge Institute, Robinson Way, Cambridge CB2 0RE, UK.
⁵ Department of Haematology, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
⁶ Department of Haematology, Wellcome and MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, Cambridgeshire CB2 0AW, UK.
⁷ Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK.
⁸ Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
⁹ NIHR BioResource, Cambridge University Hospitals NHS Foundation, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
¹⁰ Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
¹¹ Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK.
¹² Department of Public Health and Primary Care, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
¹³ Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK.
¹⁴ Medical Research Council Toxicology Unit, University of Cambridge, Gleeson Building, Tennis Court Road, Cambridge CB2 1QR, UK.
¹⁵ Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK.
¹⁶ Royal Papworth Hospital NHS Foundation Trust, Papworth Road, Cambridge CB2 0AY, UK.
¹⁷ NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.
¹⁸ Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
¹⁹ EMBL-EBI, Wellcome Genome Campus, Hinxton, CB10 1SD, UK.
²⁰ Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA.

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.

Abstract

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