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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2021
|
| Online Access: | https://hdl.handle.net/1721.1/132638 |
| _version_ | 1826217202859114496 |
|---|---|
| author | Youngs, Jonathan Provine, Nicholas M. Lim, Nicholas Sharpe, Hannah R. Amini, Ali Chen, Yi-Ling Luo, Jian Edmans, Matthew D. Zacharopoulou, Panagiota Chen, Wentao Sampson, Oliver Paton, Robert Hurt, William J. Duncan, David A. McNaughton, Anna L. Miao, Vincent N. Leaver, Susannah Wyncoll, Duncan L. A. Ball, Jonathan Hopkins, Philip Skelly, Donal T. Barnes, Eleanor Dunachie, Susanna Ogg, Graham Lambe, Teresa Pavord, Ian Shalek, Alexander K Thompson, Craig P. Xue, Luzheng Macallan, Derek C. Goulder, Philip Klenerman, Paul Bicanic, Tihana |
| author2 | Massachusetts Institute of Technology. Institute for Medical Engineering & Science |
| author_facet | Massachusetts Institute of Technology. Institute for Medical Engineering & Science Youngs, Jonathan Provine, Nicholas M. Lim, Nicholas Sharpe, Hannah R. Amini, Ali Chen, Yi-Ling Luo, Jian Edmans, Matthew D. Zacharopoulou, Panagiota Chen, Wentao Sampson, Oliver Paton, Robert Hurt, William J. Duncan, David A. McNaughton, Anna L. Miao, Vincent N. Leaver, Susannah Wyncoll, Duncan L. A. Ball, Jonathan Hopkins, Philip Skelly, Donal T. Barnes, Eleanor Dunachie, Susanna Ogg, Graham Lambe, Teresa Pavord, Ian Shalek, Alexander K Thompson, Craig P. Xue, Luzheng Macallan, Derek C. Goulder, Philip Klenerman, Paul Bicanic, Tihana |
| author_sort | Youngs, Jonathan |
| collection | MIT |
| 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<jats:sup>+</jats:sup> 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. |
| first_indexed | 2024-09-23T16:59:40Z |
| format | Article |
| id | mit-1721.1/132638 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T16:59:40Z |
| publishDate | 2021 |
| publisher | Public Library of Science (PLoS) |
| record_format | dspace |
| spelling | mit-1721.1/1326382022-09-29T22:57:05Z Identification of immune correlates of fatal outcomes in critically ill COVID-19 patients Youngs, Jonathan Provine, Nicholas M. Lim, Nicholas Sharpe, Hannah R. Amini, Ali Chen, Yi-Ling Luo, Jian Edmans, Matthew D. Zacharopoulou, Panagiota Chen, Wentao Sampson, Oliver Paton, Robert Hurt, William J. Duncan, David A. McNaughton, Anna L. Miao, Vincent N. Leaver, Susannah Wyncoll, Duncan L. A. Ball, Jonathan Hopkins, Philip Skelly, Donal T. Barnes, Eleanor Dunachie, Susanna Ogg, Graham Lambe, Teresa Pavord, Ian Shalek, Alexander K Thompson, Craig P. Xue, Luzheng Macallan, Derek C. Goulder, Philip Klenerman, Paul Bicanic, Tihana Massachusetts Institute of Technology. Institute for Medical Engineering & Science Massachusetts Institute of Technology. Department of Chemistry Koch Institute for Integrative Cancer Research at MIT 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<jats:sup>+</jats:sup> 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. 2021-09-24T18:57:41Z 2021-09-24T18:57:41Z 2021-09 2021-03 2021-09-24T17:23:55Z Article http://purl.org/eprint/type/JournalArticle 1553-7374 https://hdl.handle.net/1721.1/132638 Youngs, Jonathan et al "Identification of immune correlates of fatal outcomes in critically ill COVID-19 patients." PLoS Pathogens 17, 9 (September 2021): e1009804. en http://dx.doi.org/10.1371/journal.ppat.1009804 PLoS Pathogens Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Public Library of Science (PLoS) PLoS |
| spellingShingle | Youngs, Jonathan Provine, Nicholas M. Lim, Nicholas Sharpe, Hannah R. Amini, Ali Chen, Yi-Ling Luo, Jian Edmans, Matthew D. Zacharopoulou, Panagiota Chen, Wentao Sampson, Oliver Paton, Robert Hurt, William J. Duncan, David A. McNaughton, Anna L. Miao, Vincent N. Leaver, Susannah Wyncoll, Duncan L. A. Ball, Jonathan Hopkins, Philip Skelly, Donal T. Barnes, Eleanor Dunachie, Susanna Ogg, Graham Lambe, Teresa Pavord, Ian Shalek, Alexander K Thompson, Craig P. Xue, Luzheng Macallan, Derek C. Goulder, Philip Klenerman, Paul Bicanic, Tihana Identification of immune correlates of fatal outcomes in critically ill COVID-19 patients |
| 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://hdl.handle.net/1721.1/132638 |
| work_keys_str_mv | AT youngsjonathan identificationofimmunecorrelatesoffataloutcomesincriticallyillcovid19patients AT provinenicholasm identificationofimmunecorrelatesoffataloutcomesincriticallyillcovid19patients AT limnicholas identificationofimmunecorrelatesoffataloutcomesincriticallyillcovid19patients AT sharpehannahr identificationofimmunecorrelatesoffataloutcomesincriticallyillcovid19patients AT aminiali identificationofimmunecorrelatesoffataloutcomesincriticallyillcovid19patients AT chenyiling identificationofimmunecorrelatesoffataloutcomesincriticallyillcovid19patients AT luojian identificationofimmunecorrelatesoffataloutcomesincriticallyillcovid19patients AT edmansmatthewd identificationofimmunecorrelatesoffataloutcomesincriticallyillcovid19patients AT zacharopouloupanagiota identificationofimmunecorrelatesoffataloutcomesincriticallyillcovid19patients AT chenwentao identificationofimmunecorrelatesoffataloutcomesincriticallyillcovid19patients AT sampsonoliver identificationofimmunecorrelatesoffataloutcomesincriticallyillcovid19patients AT patonrobert identificationofimmunecorrelatesoffataloutcomesincriticallyillcovid19patients AT hurtwilliamj identificationofimmunecorrelatesoffataloutcomesincriticallyillcovid19patients AT duncandavida identificationofimmunecorrelatesoffataloutcomesincriticallyillcovid19patients AT mcnaughtonannal identificationofimmunecorrelatesoffataloutcomesincriticallyillcovid19patients AT miaovincentn identificationofimmunecorrelatesoffataloutcomesincriticallyillcovid19patients AT leaversusannah identificationofimmunecorrelatesoffataloutcomesincriticallyillcovid19patients AT wyncollduncanla identificationofimmunecorrelatesoffataloutcomesincriticallyillcovid19patients AT balljonathan identificationofimmunecorrelatesoffataloutcomesincriticallyillcovid19patients AT hopkinsphilip identificationofimmunecorrelatesoffataloutcomesincriticallyillcovid19patients AT skellydonalt identificationofimmunecorrelatesoffataloutcomesincriticallyillcovid19patients AT barneseleanor identificationofimmunecorrelatesoffataloutcomesincriticallyillcovid19patients AT dunachiesusanna identificationofimmunecorrelatesoffataloutcomesincriticallyillcovid19patients AT ogggraham identificationofimmunecorrelatesoffataloutcomesincriticallyillcovid19patients AT lambeteresa identificationofimmunecorrelatesoffataloutcomesincriticallyillcovid19patients AT pavordian identificationofimmunecorrelatesoffataloutcomesincriticallyillcovid19patients AT shalekalexanderk identificationofimmunecorrelatesoffataloutcomesincriticallyillcovid19patients AT thompsoncraigp identificationofimmunecorrelatesoffataloutcomesincriticallyillcovid19patients AT xueluzheng identificationofimmunecorrelatesoffataloutcomesincriticallyillcovid19patients AT macallanderekc identificationofimmunecorrelatesoffataloutcomesincriticallyillcovid19patients AT goulderphilip identificationofimmunecorrelatesoffataloutcomesincriticallyillcovid19patients AT klenermanpaul identificationofimmunecorrelatesoffataloutcomesincriticallyillcovid19patients AT bicanictihana identificationofimmunecorrelatesoffataloutcomesincriticallyillcovid19patients |