학술논문
Identification of immune correlates of fatal outcomes in critically ill COVID-19 patients.
Document Type
article
Author
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
Source
PLoS Pathogens, Vol 17, Iss 9, p e1009804 (2021)
Subject
Language
English
ISSN
1553-7366
1553-7374
1553-7374
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.