Identification of immune correlates of fatal outcomes in critically ill COVID-19 patients.
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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Public Library of Science (PLoS)
2021-09-01
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| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1009804&type=printable |
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| 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 |
| author_facet | 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 |
| author_sort | Jonathan Youngs |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-ae2109d6ebeb4156b32fca8cdf3e3593 |
| institution | OA Journals |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2021-09-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS Pathogens |
| spelling | doaj-art-ae2109d6ebeb4156b32fca8cdf3e35932025-08-20T02:33:18ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742021-09-01179e100980410.1371/journal.ppat.1009804Identification of immune correlates of fatal outcomes in critically ill COVID-19 patients.Jonathan YoungsNicholas M ProvineNicholas LimHannah R SharpeAli AminiYi-Ling ChenJian LuoMatthew D EdmansPanagiota ZacharopoulouWentao ChenOliver SampsonRobert PatonWilliam J HurtDavid A DuncanAnna L McNaughtonVincent N MiaoSusannah LeaverDuncan L A WyncollJonathan BallPhilip HopkinsOxford Immunology Network Covid-19 response T cell ConsortiumOxford Protective T cell Immunology for COVID-19 (OPTIC) Clinical teamDonal T SkellyEleanor BarnesSusanna DunachieGraham OggTeresa LambeIan PavordAlex K ShalekCraig P ThompsonLuzheng XueDerek C MacallanPhilip GoulderPaul KlenermanTihana BicanicPrior 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.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1009804&type=printable |
| spellingShingle | 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 Identification of immune correlates of fatal outcomes in critically ill COVID-19 patients. PLoS Pathogens |
| title | Identification of immune correlates of fatal outcomes in critically ill COVID-19 patients. |
| title_full | Identification of immune correlates of fatal outcomes in critically ill COVID-19 patients. |
| title_fullStr | Identification of immune correlates of fatal outcomes in critically ill COVID-19 patients. |
| title_full_unstemmed | Identification of immune correlates of fatal outcomes in critically ill COVID-19 patients. |
| title_short | Identification of immune correlates of fatal outcomes in critically ill COVID-19 patients. |
| title_sort | identification of immune correlates of fatal outcomes in critically ill covid 19 patients |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1009804&type=printable |
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