Immune resilience despite inflammatory stress promotes longevity and favorable health outcomes including resistance to infection

Sunil K. Ahuja (), Muthu Saravanan Manoharan, Grace C. Lee, Lyle R. McKinnon, Justin A. Meunier, Maristella Steri, Nathan Harper, Edoardo Fiorillo, Alisha M. Smith, Marcos I. Restrepo, Anne P. Branum, Matthew J. Bottomley, Valeria Orrù, Fabio Jimenez, Andrew Carrillo, Lavanya Pandranki, Caitlyn A. Winter, Lauryn A. Winter, Alvaro A. Gaitan, Alvaro G. Moreira, Elizabeth A. Walter, Guido Silvestri, Christopher L. King, Yong-Tang Zheng, Hong-Yi Zheng, Joshua Kimani, T. Blake Ball, Francis A. Plummer, Keith R. Fowke, Paul N. Harden, Kathryn J. Wood, Martin T. Ferris, Jennifer M. Lund, Mark T. Heise, Nigel Garrett, Kristen R. Canady, Salim S. Abdool Karim, Susan J. Little, Sara Gianella, Davey M. Smith, Scott Letendre, Douglas D. Richman, Francesco Cucca, Hanh Trinh, Sandra Sanchez-Reilly, Joan M. Hecht, Jose A. Cadena Zuluaga, Antonio Anzueto, Jacqueline A. Pugh, Brian K. Agan, Robert Root-Bernstein, Robert A. Clark, Jason F. Okulicz and Weijing He
Additional contact information
Sunil K. Ahuja: South Texas Veterans Health Care System
Muthu Saravanan Manoharan: South Texas Veterans Health Care System
Grace C. Lee: South Texas Veterans Health Care System
Lyle R. McKinnon: University of KwaZulu-Natal
Justin A. Meunier: South Texas Veterans Health Care System
Maristella Steri: Istituto di Ricerca Genetica e Biomedica (IRGB), CNR
Nathan Harper: South Texas Veterans Health Care System
Edoardo Fiorillo: Istituto di Ricerca Genetica e Biomedica (IRGB), CNR
Alisha M. Smith: South Texas Veterans Health Care System
Marcos I. Restrepo: South Texas Veterans Health Care System
Anne P. Branum: South Texas Veterans Health Care System
Matthew J. Bottomley: University of Oxford
Valeria Orrù: Istituto di Ricerca Genetica e Biomedica (IRGB), CNR
Fabio Jimenez: South Texas Veterans Health Care System
Andrew Carrillo: South Texas Veterans Health Care System
Lavanya Pandranki: South Texas Veterans Health Care System
Caitlyn A. Winter: South Texas Veterans Health Care System
Lauryn A. Winter: South Texas Veterans Health Care System
Alvaro A. Gaitan: South Texas Veterans Health Care System
Alvaro G. Moreira: South Texas Veterans Health Care System
Elizabeth A. Walter: South Texas Veterans Health Care System
Guido Silvestri: Emory University School of Medicine & Emory National Primate Research Center
Christopher L. King: Case Western Reserve University
Yong-Tang Zheng: Chinese Academy of Sciences
Hong-Yi Zheng: Chinese Academy of Sciences
Joshua Kimani: University of Manitoba
T. Blake Ball: University of Manitoba
Francis A. Plummer: University of Manitoba
Keith R. Fowke: University of Manitoba
Paul N. Harden: Oxford University Hospitals NHS Foundation Trust
Kathryn J. Wood: University of Oxford
Martin T. Ferris: University of North Carolina
Jennifer M. Lund: Fred Hutchinson Cancer Research Center
Mark T. Heise: University of North Carolina
Nigel Garrett: University of KwaZulu-Natal
Kristen R. Canady: South Texas Veterans Health Care System
Salim S. Abdool Karim: University of KwaZulu-Natal
Susan J. Little: University of California
Sara Gianella: University of California
Davey M. Smith: University of California
Scott Letendre: University of California
Douglas D. Richman: University of California San Diego
Francesco Cucca: Istituto di Ricerca Genetica e Biomedica (IRGB), CNR
Hanh Trinh: South Texas Veterans Health Care System
Sandra Sanchez-Reilly: South Texas Veterans Health Care System
Joan M. Hecht: South Texas Veterans Health Care System
Jose A. Cadena Zuluaga: South Texas Veterans Health Care System
Antonio Anzueto: South Texas Veterans Health Care System
Jacqueline A. Pugh: South Texas Veterans Health Care System
Brian K. Agan: Uniformed Services University of the Health Sciences
Robert Root-Bernstein: Michigan State University
Robert A. Clark: South Texas Veterans Health Care System
Jason F. Okulicz: Uniformed Services University of the Health Sciences
Weijing He: South Texas Veterans Health Care System

Nature Communications, 2023, vol. 14, issue 1, 1-31

Abstract: Abstract Some people remain healthier throughout life than others but the underlying reasons are poorly understood. Here we hypothesize this advantage is attributable in part to optimal immune resilience (IR), defined as the capacity to preserve and/or rapidly restore immune functions that promote disease resistance (immunocompetence) and control inflammation in infectious diseases as well as other causes of inflammatory stress. We gauge IR levels with two distinct peripheral blood metrics that quantify the balance between (i) CD8+ and CD4+ T-cell levels and (ii) gene expression signatures tracking longevity-associated immunocompetence and mortality-associated inflammation. Profiles of IR metrics in ~48,500 individuals collectively indicate that some persons resist degradation of IR both during aging and when challenged with varied inflammatory stressors. With this resistance, preservation of optimal IR tracked (i) a lower risk of HIV acquisition, AIDS development, symptomatic influenza infection, and recurrent skin cancer; (ii) survival during COVID-19 and sepsis; and (iii) longevity. IR degradation is potentially reversible by decreasing inflammatory stress. Overall, we show that optimal IR is a trait observed across the age spectrum, more common in females, and aligned with a specific immunocompetence-inflammation balance linked to favorable immunity-dependent health outcomes. IR metrics and mechanisms have utility both as biomarkers for measuring immune health and for improving health outcomes.

Date: 2023
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DOI: 10.1038/s41467-023-38238-6

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