Proteomic analysis of circulating immune cells identifies cellular phenotypes associated with COVID-19 severity
Martin Potts,
Alice Fletcher-Etherington,
Katie Nightingale,
Federica Mescia,
Laura Bergamaschi,
Fernando J. Calero-Nieto,
Robin Antrobus,
James Williamson,
Harriet Parsons,
Edward L. Huttlin,
Nathalie Kingston,
Berthold Göttgens,
John R. Bradley,
Paul J. Lehner,
Nicholas J. Matheson,
Kenneth G.C. Smith,
Mark R. Wills,
Paul A. Lyons,
Michael P. Weekes
Affiliations
Martin Potts
Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK; Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK
Alice Fletcher-Etherington
Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK; Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK
Katie Nightingale
Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK; Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK
Federica Mescia
Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK
Laura Bergamaschi
Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK
Fernando J. Calero-Nieto
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
Robin Antrobus
Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK; Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK
James Williamson
Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK
Harriet Parsons
Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK; Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK
Edward L. Huttlin
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
Nathalie Kingston
NIHR BioResource, Cambridge University Hospitals NHS Foundation, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Department of Haematology, University of Cambridge, Cambridge CB2 0AW, UK
Berthold Göttgens
Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 OAW, UK
John R. Bradley
Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK; NIHR BioResource, Cambridge University Hospitals NHS Foundation, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
Paul J. Lehner
Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK
Nicholas J. Matheson
Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK; NHS Blood and Transplant, Cambridge CB2 0PT, UK
Kenneth G.C. Smith
Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK
Mark R. Wills
Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK
Paul A. Lyons
Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK
Michael P. Weekes
Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK; Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK; Corresponding author
Summary: Certain serum proteins, including C-reactive protein (CRP) and D-dimer, have prognostic value in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Nonetheless, these factors are non-specific, providing limited mechanistic insight into the peripheral blood mononuclear cell (PBMC) populations that drive the pathogenesis of severe COVID-19. To identify cellular phenotypes associated with disease, we performed a comprehensive, unbiased analysis of total and plasma-membrane PBMC proteomes from 40 unvaccinated individuals with SARS-CoV-2, spanning the whole disease spectrum. Combined with RNA sequencing (RNA-seq) and flow cytometry from the same donors, we define a comprehensive multi-omic profile for each severity level, revealing that immune-cell dysregulation progresses with increasing disease. The cell-surface proteins CEACAMs1, 6, and 8, CD177, CD63, and CD89 are strongly associated with severe COVID-19, corresponding to the emergence of atypical CD3+CD4+CEACAM1/6/8+CD177+CD63+CD89+ and CD16+CEACAM1/6/8+ mononuclear cells. Utilization of these markers may facilitate real-time patient assessment by flow cytometry and identify immune populations that could be targeted to ameliorate immunopathology.
