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Identification of immune correlates of fatal outcomes in critically ill COVID-19 patients

DOI: 10.1371/journal.ppat.1009804 DOI Help

Authors: Jonathan Youngs (University of London; St. George’s Hospital NHS Trust) , Nicholas M. Provine (University of Oxford) , Nicholas Lim (University of Oxford) , Hannah R. Sharpe (Jenner Institute, University of Oxford) , Ali Amini (University of Oxford) , Yi-Ling Chen (University of Oxford) , Jian Luo (University of Oxford) , Matthew D. Edmans (University of Oxford) , Panagiota Zacharopoulou (University of Oxford) , Wentao Chen (University of Oxford) , Oliver Sampson (University of Oxford) , Robert Paton (University of Oxford) , William J. Hurt (St. George’s University of London) , David A. Duncan (University of Oxford; Diamond Light Source) , Anna L. Mcnaughton (University of Oxford) , Vincent N. Miao (Massachusetts Institute of Technology) , Susannah Leaver (St George’s University Hospital NHS Foundation Trust,) , Duncan L. A. Wyncoll (Guy’s and St Thomas’ Hospital NHS Foundation Trust) , Jonathan Ball (St George’s University Hospital NHS Foundation Trust) , Philip Hopkins (King’s College, London) , Donal T. Skelly (University of Oxford) , Eleanor Barnes (University of Oxford) , Susanna Dunachie (University of Oxford) , Graham Ogg (University of Oxford) , Teresa Lambe (University of Oxford) , Ian Pavord (University of Oxford) , Alex K. Shalek (Massachusetts Institute of Technology; Broad Institute of MIT and Harvard, Cambridge) , Craig P. Thompson (University of Oxford) , Luzheng Xue (University of Oxford) , Derek C. Macallan (St. George’s University of London; St. George’s Hospital NHS Trust) , Philip Goulder (University of Oxford) , Paul Klenerman (University of Oxford) , Tihana Bicanic (St. George’s University of London; St. George’s Hospital NHS Trust)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Plos Pathogens , VOL 17

State: Published (Approved)
Published: September 2021

Open Access Open Access

Abstract: Prior studies have demonstrated that immunologic dysfunction underpins severe illness in COVID-19 patients, but have lacked an in-depth analysis of the immunologic drivers of death in the most critically ill patients. We performed immunophenotyping of viral antigen-specific and unconventional T cell responses, neutralizing antibodies, and serum proteins in critically ill patients with SARS-CoV-2 infection, using influenza infection, SARS-CoV-2-convalescent health care workers, and healthy adults as controls. We identify mucosal-associated invariant T (MAIT) cell activation as an independent and significant predictor of death in COVID-19 (HR = 5.92, 95% CI = 2.49–14.1). MAIT cell activation correlates with several other mortality-associated immunologic measures including broad activation of CD8+ T cells and non-Vδ2 γδT cells, and elevated levels of cytokines and chemokines, including GM-CSF, CXCL10, CCL2, and IL-6. MAIT cell activation is also a predictor of disease severity in influenza (ECMO/death HR = 4.43, 95% CI = 1.08–18.2). Single-cell RNA-sequencing reveals a shift from focused IFNα-driven signals in COVID-19 ICU patients who survive to broad pro-inflammatory responses in fatal COVID-19 –a feature not observed in severe influenza. We conclude that fatal COVID-19 infection is driven by uncoordinated inflammatory responses that drive a hierarchy of T cell activation, elements of which can serve as prognostic indicators and potential targets for immune intervention.

Journal Keywords: COVID 19; Influenza; Cytokines; T helper cells; Cytotoxic T cells; Intensive care units; Virus testing; Serum proteins

Diamond Keywords: COVID-19; Viruses

Subject Areas: Biology and Bio-materials


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Added On: 21/09/2021 14:24

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journal.ppat.1009804.pdf

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Life Sciences & Biotech Health & Wellbeing Infectious Diseases Pathogens

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