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.
| Original language | English |
|---|---|
| Article number | 3286 |
| Journal | Nature Communications |
| Volume | 14 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 2023 |
| Externally published | Yes |
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In: Nature Communications, Vol. 14, No. 1, 3286, 12.2023.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Immune resilience despite inflammatory stress promotes longevity and favorable health outcomes including resistance to infection
AU - South Texas Veterans Health Care System COVID-19 Team
AU - Ahuja, Sunil K.
AU - Manoharan, Muthu Saravanan
AU - Lee, Grace C.
AU - McKinnon, Lyle R.
AU - Meunier, Justin A.
AU - Steri, Maristella
AU - Harper, Nathan
AU - Fiorillo, Edoardo
AU - Smith, Alisha M.
AU - Restrepo, Marcos I.
AU - Branum, Anne P.
AU - Bottomley, Matthew J.
AU - Orrù, Valeria
AU - Jimenez, Fabio
AU - Carrillo, Andrew
AU - Pandranki, Lavanya
AU - Winter, Caitlyn A.
AU - Winter, Lauryn A.
AU - Gaitan, Alvaro A.
AU - Moreira, Alvaro G.
AU - Walter, Elizabeth A.
AU - Silvestri, Guido
AU - King, Christopher L.
AU - Zheng, Yong Tang
AU - Zheng, Hong Yi
AU - Kimani, Joshua
AU - Blake Ball, T.
AU - Plummer, Francis A.
AU - Fowke, Keith R.
AU - Harden, Paul N.
AU - Wood, Kathryn J.
AU - Ferris, Martin T.
AU - Lund, Jennifer M.
AU - Heise, Mark T.
AU - Garrett, Nigel
AU - Canady, Kristen R.
AU - Abdool Karim, Salim S.
AU - Little, Susan J.
AU - Gianella, Sara
AU - Smith, Davey M.
AU - Letendre, Scott
AU - Richman, Douglas D.
AU - Cucca, Francesco
AU - Trinh, Hanh
AU - Sanchez-Reilly, Sandra
AU - Hecht, Joan M.
AU - Cadena Zuluaga, Jose A.
AU - Anzueto, Antonio
AU - Agan, Brian K.
AU - Okulicz, Jason F.
N1 - Funding Information: The HIV-seronegative UCSD cohort was accessed from HIV Neurobehavioral Research Center, UCSD, and derived from the following three resources: (a) those who enrolled as a normative population for ongoing studies funded by the National Institute of Mental Health; (b) those who enrolled as a normative population for studies funded by the National Institute on Drug Abuse; and (c) those who enrolled as HIV– users of recreational drugs for studies funded by the National Institute on Drug Abuse. In the present study, we evaluated 759 participants pooled from the three abovementioned sources. Details provided in Supplementary Information Section . Funding Information: The two main sources of funding for the data presented herein are those awarded to S.K.A. and J.F.O. S.K.A. was supported by grants from the Veterans Affairs (VA) [VA Research Center for AIDS and HIV Infection, VA Center for Personalized Medicine (IP1 CX000875-01A1), and a VA MERIT award]; the National Institutes of Health (NIH) MERIT award (R37AI046326); the Doris Duke Distinguished Clinical Scientist Award; the Elizabeth Glaser Pediatric AIDS Foundation; the Burroughs Wellcome Clinical Scientist Award in Translational Research; and the Senior Scholar Award from the Max and Minnie Tomerlin Voelcker Fund. The work was also supported, in part, by an award jointly funded by NIAID/NIH (#AAI20042-001) and the Veterans Affairs (COVID19-8100-01) awarded to S.K.A. and M.I.R. A portion of the material presented is based on research sponsored by the U.S. Air Force under agreement number FA8650-17-2-6816 (United States Air Force 59th Medical Wing Intramural Award to J.F.O.). This study was also supported by the Infectious Disease Clinical Research Program (IDCRP), a Department of Defense program executed by the Uniformed Services University of the Health Sciences through a cooperative agreement with The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. (H.J.F). The IDCRP has been funded in whole, or in part, with federal funds from the National Institute of Allergy and Infectious Diseases, NIH, under Inter‐Agency Agreement (Y1-AI-5072). The SardiNIA study was supported in part by the Intramural Research Program of the NIH, National Institute on Aging, with contracts N01-AG-1-2109 and HHSN271201100005C; by Italian grants FISM 2011/R/13, FaReBio2011, Funds MIUR/CNR for Rare Diseases and Molecular Screening, CNR/DSB flagship INTEROMICS, PNR/CNR Aging Program 2012-2014; European Union’s Horizon 2020 Research and Innovation Programme under grant agreement 633964; Giovani Ricercatori 2007 (D.lgs 502/92); and Legge Regionale 30 giugno 2011 n.12, articolo 3, comma 3 (to F.C.). The Kenya Majengo Observational (female sex worker) Cohort Study was supported by grants from the NIH (R01 AI56980), the Canadian Institutes of Health Research (HOP-43135), the Bill and Melinda Gates Foundation (39673), and the CIHR through the Grand Challenges in Global Health Initiative (to F.A.P.). LRM was supported by a CIHR Biomedical/Clinical HIV/AIDS Research Fellowship and the International Infectious Diseases and Global Health Training Program. The HIV- UCSD cohort was supported by National Institute of Mental Health (NIMH) P30 grant (PI: R. Heaton, MH62512), MARC from National Institute on Drug Abuse P50 grant (PI: I. Grant DA26306), and ProM from NIMH R01 grant (PI: S. Woods, MH73419). S.L. was supported by K24 MH097673 from the National Institute of Mental Health. The renal transplant recipient cohort and MJB were supported by grants from the Wellcome Trust (Clinical Training Fellowship) and Oxford Hospitals Research Services Committee. M.J.B. acknowledges the support of the UK National Institute for Health Research through the Local Clinical Research Network. The HIV- Kenyan Schistosoma haematobium children cohort was supported by NIH grant AI064687 (C.L.K.). The primary HIV infection cohort and D.M.S., S.J.L., and D.D.R. were supported by NIH grants AI43638, AI074621, AI106039, and MH100974; Inter-Agency Agreement Y1-AI-5072; and the California HIV Research Program RN07-SD-702. The Sooty mangabey cohort and GS were supported by NIH grant A1 R3766998. The Chinese rhesus macaque study was supported by the National Basic Research Program of China (2012CBA01305), the Knowledge Innovation Program of CAS (KSCX2-EW-R-13), the National Natural Science Foundation of China (81172876, 81273251, U1202228), and the Key Scientific and Technological Program of China (2013ZX10001-002, 2012ZX10001-007). The CC mice study and J.M.L. were supported by NIH grants AI100625, AI096968, and AI087657. AMS was supported by the NIH T32DE014318 COSTAR institutional research training grant. K.R.C. was supported by NIH grant T32GM113896/STXMSTP. This work was also supported by NIH grant 1UL1 TR002645 (Clinical and Translational Science Award to RAC). G.C.L. was supported by the NIH K23-AG066933. We thank participants of the cohorts, other members of the Ahuja lab that contributed to the study, Dr. Kimberly Summers for help with study approvals, and Donna Thordsen for critical reading of the manuscript. Funding Information: The two main sources of funding for the data presented herein are those awarded to S.K.A. and J.F.O. S.K.A. was supported by grants from the Veterans Affairs (VA) [VA Research Center for AIDS and HIV Infection, VA Center for Personalized Medicine (IP1 CX000875-01A1), and a VA MERIT award]; the National Institutes of Health (NIH) MERIT award (R37AI046326); the Doris Duke Distinguished Clinical Scientist Award; the Elizabeth Glaser Pediatric AIDS Foundation; the Burroughs Wellcome Clinical Scientist Award in Translational Research; and the Senior Scholar Award from the Max and Minnie Tomerlin Voelcker Fund. The work was also supported, in part, by an award jointly funded by NIAID/NIH (#AAI20042-001) and the Veterans Affairs (COVID19-8100-01) awarded to S.K.A. and M.I.R. A portion of the material presented is based on research sponsored by the U.S. Air Force under agreement number FA8650-17-2-6816 (United States Air Force 59th Medical Wing Intramural Award to J.F.O.). This study was also supported by the Infectious Disease Clinical Research Program (IDCRP), a Department of Defense program executed by the Uniformed Services University of the Health Sciences through a cooperative agreement with The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. (H.J.F). The IDCRP has been funded in whole, or in part, with federal funds from the National Institute of Allergy and Infectious Diseases, NIH, under Inter‐Agency Agreement (Y1-AI-5072). The SardiNIA study was supported in part by the Intramural Research Program of the NIH, National Institute on Aging, with contracts N01-AG-1-2109 and HHSN271201100005C; by Italian grants FISM 2011/R/13, FaReBio2011, Funds MIUR/CNR for Rare Diseases and Molecular Screening, CNR/DSB flagship INTEROMICS, PNR/CNR Aging Program 2012-2014; European Union’s Horizon 2020 Research and Innovation Programme under grant agreement 633964; Giovani Ricercatori 2007 (D.lgs 502/92); and Legge Regionale 30 giugno 2011 n.12, articolo 3, comma 3 (to F.C.). The Kenya Majengo Observational (female sex worker) Cohort Study was supported by grants from the NIH (R01 AI56980), the Canadian Institutes of Health Research (HOP-43135), the Bill and Melinda Gates Foundation (39673), and the CIHR through the Grand Challenges in Global Health Initiative (to F.A.P.). LRM was supported by a CIHR Biomedical/Clinical HIV/AIDS Research Fellowship and the International Infectious Diseases and Global Health Training Program. The HIV- UCSD cohort was supported by National Institute of Mental Health (NIMH) P30 grant (PI: R. Heaton, MH62512), MARC from National Institute on Drug Abuse P50 grant (PI: I. Grant DA26306), and ProM from NIMH R01 grant (PI: S. Woods, MH73419). S.L. was supported by K24 MH097673 from the National Institute of Mental Health. The renal transplant recipient cohort and MJB were supported by grants from the Wellcome Trust (Clinical Training Fellowship) and Oxford Hospitals Research Services Committee. M.J.B. acknowledges the support of the UK National Institute for Health Research through the Local Clinical Research Network. The HIV- Kenyan Schistosoma haematobium children cohort was supported by NIH grant AI064687 (C.L.K.). The primary HIV infection cohort and D.M.S., S.J.L., and D.D.R. were supported by NIH grants AI43638, AI074621, AI106039, and MH100974; Inter-Agency Agreement Y1-AI-5072; and the California HIV Research Program RN07-SD-702. The Sooty mangabey cohort and GS were supported by NIH grant A1 R3766998. The Chinese rhesus macaque study was supported by the National Basic Research Program of China (2012CBA01305), the Knowledge Innovation Program of CAS (KSCX2-EW-R-13), the National Natural Science Foundation of China (81172876, 81273251, U1202228), and the Key Scientific and Technological Program of China (2013ZX10001-002, 2012ZX10001-007). The CC mice study and J.M.L. were supported by NIH grants AI100625, AI096968, and AI087657. AMS was supported by the NIH T32DE014318 COSTAR institutional research training grant. K.R.C. was supported by NIH grant T32GM113896/STXMSTP. This work was also supported by NIH grant 1UL1 TR002645 (Clinical and Translational Science Award to RAC). G.C.L. was supported by the NIH K23-AG066933. We thank participants of the cohorts, other members of the Ahuja lab that contributed to the study, Dr. Kimberly Summers for help with study approvals, and Donna Thordsen for critical reading of the manuscript. Framingham Heart Study dbGaP Acknowledgement Statement: The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University (Contract No. N01-HC-25195 and HHSN268201500001I). This manuscript was not prepared in collaboration with investigators of the Framingham Heart Study and does not necessarily reflect the opinions or views of the Framingham Heart Study, Boston University, or NHLBI. Additional funding for SABRe was provided by Division of Intramural Research, NHLBI, and Center for Population Studies, NHLBI. Disclaimer is noted in the Supplementary Information. Funding Information: Framingham Heart Study dbGaP Acknowledgement Statement: The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University (Contract No. N01-HC-25195 and HHSN268201500001I). This manuscript was not prepared in collaboration with investigators of the Framingham Heart Study and does not necessarily reflect the opinions or views of the Framingham Heart Study, Boston University, or NHLBI. Additional funding for SABRe was provided by Division of Intramural Research, NHLBI, and Center for Population Studies, NHLBI. Publisher Copyright: © 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85161851456&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-38238-6
DO - 10.1038/s41467-023-38238-6
M3 - Article
C2 - 37311745
AN - SCOPUS:85161851456
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3286
ER -