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

Biology Biology
Genomics Genomics
Immunology Immunology
Infectious Disease Infectious Disease
Alex K. Shalek Alex K. Shalek
Vincent Miao Vincent Miao

Youngs et al.▾ Youngs, J.*, Provine, N.M.*, Lim, N.*, ID3☯, Sharpe, H.R.#, Amini, A.#, Chen, Y.-L., Luo, J.#, Edmans, M.D., Zacharopoulou, P., Chen, W., Sampson, O., Paton, R., Hurt, W.J., Duncan, D.A., McNaughton, A.L., Miao, V.N., Leaver, S., Wyncoll, D.L.A., Ball, J., Hopkins, P., Oxford Immunology Network Covid-19 response T cell Consortium, Oxford Protective T cell Immunology for COVID-19 (OPTIC) Clinical team, Skelly, D.T., Barnes, E., Dunachie, S., Ogg, G., Lambe, T., Pavord, I., ID7, Shalek, A.K., Thompson, C.P., Xue, L., Macallan, D.C., Goulder, P.$, Klenerman, P.$, Bicanic, T.$

PLOS Pathogens , Volume 17

September, 2021


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.