Journal
PLOS PATHOGENS
Volume 17, Issue 9, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.ppat.1009804
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Funding
- Wellcome Clinical Training Fellowship [216417/Z/19/Z]
- Wellcome four-year PhD studentship through the IITM Programme [108869/Z/15/Z, 203805/Z/16/Z]
- NIHR Academic Clinical Fellow programme in Oxford
- NIHR Senior Fellowship
- NIHR Biomedical Research Centre (Oxford)
- NIHR Global Research Professorship
- Wellcome [WT109965MA]
- UK Coronavirus Immunology Consortium (UK-CIC)
- NIHR [COV19-RECPLAS]
- UK Department of Health and Social Care as part of the PITCH (Protective Immunity from T cells to Covid19 in Health workers) Consortium
- Huo Family Foundation
- National Core Study: Immunity (NCSi4P programme) Optimal cellular assays for SARS-CoV-2 T cell, B cell and innate immunity
- Gilead UK and Ireland Fellowship [07512]
- Wellcome Trust [203805/Z/16/Z] Funding Source: Wellcome Trust
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The activation of MAIT cells in critically ill COVID-19 patients is a significant predictor of death and is associated with other mortality-associated immunologic measures. Additionally, a shift from focused IFN alpha-driven signals to broad pro-inflammatory responses in fatal COVID-19 patients was observed, which was not seen in severe influenza cases. The study identified key potential biomarkers and targetable pathways in critical viral illnesses, shared between influenza and COVID-19, with some unique to each infection.
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-V delta 2 gamma delta T 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 IFN alpha-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. Author summaryWe examined the immune abnormalities linked to critical illness and death in COVID-19 patients on ICU, performing immunophenotyping of viral antigen-specific and unconventional T cell responses, together with studies of neutralizing antibodies, and serum proteins. We compared these findings to a parallel set of patients with severe influenza. From this screen we identified mucosal-associated invariant T (MAIT) cell activation as an independent and significant predictor of death in COVID-19. MAIT cell activation correlated with several other mortality-associated immunologic measures including elevated levels of cytokines and chemokines, such as GM-CSF and CXCL10. MAIT cell activation is also a predictor of disease severity in influenza. Single-cell RNA-sequencing revealed a shift from focused IFN alpha-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. Overall we observed key potential biomarkers and targetable pathways in critical viral illness, many shared between influenza and COVID-19 and some unique to each infection.
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