Distinctive evolution of alveolar T cell responses is associated with clinical outcomes in unvaccinated patients with SARS-CoV-2 pneumonia

The NU SCRIPT Study Investigators

doi:10.1038/s41590-024-01914-w

Distinctive evolution of alveolar T cell responses is associated with clinical outcomes in unvaccinated patients with SARS-CoV-2 pneumonia

The NU SCRIPT Study Investigators

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

The evolution of T cell molecular signatures in the distal lung of patients with severe pneumonia is understudied. Here, we analyzed T cell subsets in longitudinal bronchoalveolar lavage fluid samples from 273 patients with severe pneumonia, including unvaccinated patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or with respiratory failure not linked to pneumonia. In patients with SARS-CoV-2 pneumonia, activation of interferon signaling pathways, low activation of the NF-κB pathway and preferential targeting of spike and nucleocapsid proteins early after intubation were associated with favorable outcomes, whereas loss of interferon signaling, activation of NF-κB-driven programs and specificity for the ORF1ab complex late in disease were associated with mortality. These results suggest that in patients with severe SARS-CoV-2 pneumonia, alveolar T cell interferon responses targeting structural SARS-CoV-2 proteins characterize individuals who recover, whereas responses against nonstructural proteins and activation of NF-κB are associated with poor outcomes.

Original language	English (US)
Pages (from-to)	1607-1622
Number of pages	16
Journal	Nature Immunology
Volume	25
Issue number	9
DOIs	https://doi.org/10.1038/s41590-024-01914-w
State	Accepted/In press - 2024

Funding

We thank the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago for the use of the Flow Cytometry Core Facility. The Lurie Cancer Center is supported, in part, by an NCI Cancer Center Support Grant P30 CA060553. This research was supported, in part, through the computational resources and staff contributions provided for the Quest High-Performance Computing Facility at Northwestern University, which is jointly supported by the Office of the Provost, the Office for Research and Northwestern University Information Technology. We acknowledge the support of The Simpson Querrey Lung Institute for Translational Sciences at Northwestern University, the Dixon Translational Research Grants Initiative at Northwestern Medicine and the Northwestern University Clinical and Translational Sciences Institute (UL1TR001422). This work was also supported by the Chicago Biomedical Consortium with support from the Searle Funds at The Chicago Community Trust. N.S.M. was supported by AHA 24PRE1196998. C.A.G. was supported by T32HL076139 and F32HL162377. R.A.G. was funded by NIH grants T32AG020506 and F31AG071225 and Schmidt Science Fellows. A.V.M. was supported by NIH grants U19AI135964, U19AI181102, P01AG049665, P01HL154998, R01HL153312, R01HL158139, R01ES034350 and R21AG075423. R.G.W. was supported by NIH grants U19AI135964, U01TR003528, P01HL154998, R01HL149883 and R01LM013337. G.R.S.B. was supported by a Chicago Biomedical Consortium grant, Northwestern University Dixon Translational Science Award and Simpson Querrey Lung Institute for Translational Science and NIH grants AG049665, HL154998, HL14575, HL158139, HL147290, AG075423 and AI135964 and The Veterans Administration award I01CX001777. B.D.S. was supported by NIH awards R01HL149883, R01HL153122, P01HL154998, P01AG049665, U19AI135964 and U19AI181102. L.M.-N. was supported by the Parker B. Francis Opportunity Award and NIH awards K08HL15935 and U19AI135964.

ASJC Scopus subject areas

Immunology and Allergy
Immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41590-024-01914-w

Cite this

@article{473fe160cc2b4e04863052ffa1a9eedb,

title = "Distinctive evolution of alveolar T cell responses is associated with clinical outcomes in unvaccinated patients with SARS-CoV-2 pneumonia",

abstract = "The evolution of T cell molecular signatures in the distal lung of patients with severe pneumonia is understudied. Here, we analyzed T cell subsets in longitudinal bronchoalveolar lavage fluid samples from 273 patients with severe pneumonia, including unvaccinated patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or with respiratory failure not linked to pneumonia. In patients with SARS-CoV-2 pneumonia, activation of interferon signaling pathways, low activation of the NF-κB pathway and preferential targeting of spike and nucleocapsid proteins early after intubation were associated with favorable outcomes, whereas loss of interferon signaling, activation of NF-κB-driven programs and specificity for the ORF1ab complex late in disease were associated with mortality. These results suggest that in patients with severe SARS-CoV-2 pneumonia, alveolar T cell interferon responses targeting structural SARS-CoV-2 proteins characterize individuals who recover, whereas responses against nonstructural proteins and activation of NF-κB are associated with poor outcomes.",

author = "{The NU SCRIPT Study Investigators} and Ziyou Ren and Gao, {Catherine A.} and Malsin, {Elizabeth S.} and Hiam Abdala-Valencia and Suchitra Swaminathan and Ozer, {Egon A.} and Ramon Lorenzo-Redondo and Judd Hultquist and Misharin, {Alexander V.} and Wunderink, {Richard G.} and Budinger, {G. R.Scott} and Singer, {Benjamin D.} and Luisa Morales-Nebreda and Hiam Abdala-Valencia and Judd Hultquist and Alexander, {Michael J.} and Bailey, {Joseph I.} and Bartom, {Elizabeth T.} and Ankit Bharat and Chandel, {Navdeep S.} and John Coleman and Cuttica, {Michael J.} and Fiala, {Justin A.} and Gates, {Khalilah L.} and Gottardi, {Cara J.} and Han, {Seung Hye} and Hartmann, {Erica Marie} and Hauser, {Alan R.} and Horvath, {Curt M.} and Manu Jain and Kadar, {Rachel B.} and Ravi Kalhan and Kamp, {David W.} and Manoj Kandpal and Kruser, {Jacqueline M.} and Lomasney, {Jon W.} and Daniel Meza and Mylvaganam, {Ruben J.} and Prickett, {Michelle H.} and Chao Qi and Ridge, {Karen M.} and Rosenberg, {Sharon R.} and Timothy Rowe and Russell, {Susan R.} and Sala, {Marc A.} and Schroedl, {Clara J.} and Seed, {Patrick C.} and Shanes, {Elisheva D.} and Ali Shilatifard and Sean Smith and Sporn, {Peter H.S.} and Justin Starren and Thomas Stoeger and Sznajder, {Jacob I.} and Rade Tomic and Betty Tran and Walter, {James M.} and Firas Wehbe and Winter, {Deborah R.} and Wolfe, {Lisa F.} and Yeldandi, {Anjana V.}",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.",

year = "2024",

doi = "10.1038/s41590-024-01914-w",

language = "English (US)",

volume = "25",

pages = "1607--1622",

journal = "Nature Immunology",

issn = "1529-2908",

publisher = "Nature Research",

number = "9",

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T1 - Distinctive evolution of alveolar T cell responses is associated with clinical outcomes in unvaccinated patients with SARS-CoV-2 pneumonia

AU - The NU SCRIPT Study Investigators

AU - Ren, Ziyou

AU - Gao, Catherine A.

AU - Malsin, Elizabeth S.

AU - Abdala-Valencia, Hiam

AU - Swaminathan, Suchitra

AU - Ozer, Egon A.

AU - Lorenzo-Redondo, Ramon

AU - Hultquist, Judd

AU - Misharin, Alexander V.

AU - Wunderink, Richard G.

AU - Budinger, G. R.Scott

AU - Singer, Benjamin D.

AU - Morales-Nebreda, Luisa

AU - Abdala-Valencia, Hiam

AU - Hultquist, Judd

AU - Alexander, Michael J.

AU - Bailey, Joseph I.

AU - Bartom, Elizabeth T.

AU - Bharat, Ankit

AU - Chandel, Navdeep S.

AU - Coleman, John

AU - Cuttica, Michael J.

AU - Fiala, Justin A.

AU - Gates, Khalilah L.

AU - Gottardi, Cara J.

AU - Han, Seung Hye

AU - Hartmann, Erica Marie

AU - Hauser, Alan R.

AU - Horvath, Curt M.

AU - Jain, Manu

AU - Kadar, Rachel B.

AU - Kalhan, Ravi

AU - Kamp, David W.

AU - Kandpal, Manoj

AU - Kruser, Jacqueline M.

AU - Lomasney, Jon W.

AU - Meza, Daniel

AU - Mylvaganam, Ruben J.

AU - Prickett, Michelle H.

AU - Qi, Chao

AU - Ridge, Karen M.

AU - Rosenberg, Sharon R.

AU - Rowe, Timothy

AU - Russell, Susan R.

AU - Sala, Marc A.

AU - Schroedl, Clara J.

AU - Seed, Patrick C.

AU - Shanes, Elisheva D.

AU - Shilatifard, Ali

AU - Smith, Sean

AU - Sporn, Peter H.S.

AU - Starren, Justin

AU - Stoeger, Thomas

AU - Sznajder, Jacob I.

AU - Tomic, Rade

AU - Tran, Betty

AU - Walter, James M.

AU - Wehbe, Firas

AU - Winter, Deborah R.

AU - Wolfe, Lisa F.

AU - Yeldandi, Anjana V.

PY - 2024

Y1 - 2024

N2 - The evolution of T cell molecular signatures in the distal lung of patients with severe pneumonia is understudied. Here, we analyzed T cell subsets in longitudinal bronchoalveolar lavage fluid samples from 273 patients with severe pneumonia, including unvaccinated patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or with respiratory failure not linked to pneumonia. In patients with SARS-CoV-2 pneumonia, activation of interferon signaling pathways, low activation of the NF-κB pathway and preferential targeting of spike and nucleocapsid proteins early after intubation were associated with favorable outcomes, whereas loss of interferon signaling, activation of NF-κB-driven programs and specificity for the ORF1ab complex late in disease were associated with mortality. These results suggest that in patients with severe SARS-CoV-2 pneumonia, alveolar T cell interferon responses targeting structural SARS-CoV-2 proteins characterize individuals who recover, whereas responses against nonstructural proteins and activation of NF-κB are associated with poor outcomes.

AB - The evolution of T cell molecular signatures in the distal lung of patients with severe pneumonia is understudied. Here, we analyzed T cell subsets in longitudinal bronchoalveolar lavage fluid samples from 273 patients with severe pneumonia, including unvaccinated patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or with respiratory failure not linked to pneumonia. In patients with SARS-CoV-2 pneumonia, activation of interferon signaling pathways, low activation of the NF-κB pathway and preferential targeting of spike and nucleocapsid proteins early after intubation were associated with favorable outcomes, whereas loss of interferon signaling, activation of NF-κB-driven programs and specificity for the ORF1ab complex late in disease were associated with mortality. These results suggest that in patients with severe SARS-CoV-2 pneumonia, alveolar T cell interferon responses targeting structural SARS-CoV-2 proteins characterize individuals who recover, whereas responses against nonstructural proteins and activation of NF-κB are associated with poor outcomes.

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AN - SCOPUS:85202459324

SN - 1529-2908

VL - 25

SP - 1607

EP - 1622

JO - Nature Immunology

JF - Nature Immunology

IS - 9

ER -

Distinctive evolution of alveolar T cell responses is associated with clinical outcomes in unvaccinated patients with SARS-CoV-2 pneumonia

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

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