TY - JOUR
T1 - Identification of immune correlates of fatal outcomes in critically ill COVID-19 patients
AU - Youngs, Jonathan
AU - Provine, Nicholas M.
AU - Lim, Nicholas
AU - Sharpe, Hannah R.
AU - Amini, Ali
AU - Chen, Yi Ling
AU - Luo, Jian
AU - Edmans, Matthew D.
AU - Zacharopoulou, Panagiota
AU - Chen, Wentao
AU - Sampson, Oliver
AU - Paton, Robert
AU - Hurt, William J.
AU - Duncan, David A.
AU - McNaughton, Anna L.
AU - Miao, Vincent N.
AU - Leaver, Susannah
AU - Wyncoll, Duncan L.A.
AU - Ball, Jonathan
AU - Hopkins, Philip
AU - Skelly, Donal T.
AU - Barnes, Eleanor
AU - Dunachie, Susanna
AU - Ogg, Graham
AU - Lambe, Teresa
AU - Pavord, Ian
AU - Shalek, Alex K.
AU - Thompson, Craig P.
AU - Xue, Luzheng
AU - Macallan, Derek C.
AU - Goulder, Philip
AU - Klenerman, Paul
AU - Bicanic, Tihana
N1 - Publisher Copyright:
Copyright: © 2021 Youngs et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2021/9
Y1 - 2021/9
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85115241915
U2 - 10.1371/journal.ppat.1009804
DO - 10.1371/journal.ppat.1009804
M3 - Article
C2 - 34529726
AN - SCOPUS:85115241915
SN - 1553-7366
VL - 17
JO - PLoS Pathogens
JF - PLoS Pathogens
IS - 9
M1 - e1009804
ER -