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

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

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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...

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Main Authors: Jonathan Youngs, Nicholas M Provine, Nicholas Lim, Hannah R Sharpe, Ali Amini, Yi-Ling Chen, Jian Luo, Matthew D Edmans, Panagiota Zacharopoulou, Wentao Chen, Oliver Sampson, Robert Paton, William J Hurt, David A Duncan, Anna L McNaughton, Vincent N Miao, Susannah Leaver, Duncan L A Wyncoll, Jonathan Ball, Philip Hopkins, Oxford Immunology Network Covid-19 response T cell Consortium, Oxford Protective T cell Immunology for COVID-19 (OPTIC) Clinical team, Donal T Skelly, Eleanor Barnes, Susanna Dunachie, Graham Ogg, Teresa Lambe, Ian Pavord, Alex K Shalek, Craig P Thompson, Luzheng Xue, Derek C Macallan, Philip Goulder, Paul Klenerman, Tihana Bicanic
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2021-09-01
Series:PLoS Pathogens
Online Access:https://doi.org/10.1371/journal.ppat.1009804
Description
Summary: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.
ISSN:1553-7366
1553-7374

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