TY - JOUR
T1 - Lifelong cytomegalovirus and early-LIFE irradiation synergistically potentiate age-related defects in response to vaccination and infection
AU - Pugh, Jason L.
AU - Coplen, Christopher P.
AU - Sukhina, Alona S.
AU - Uhrlaub, Jennifer L
AU - Padilla-Torres, Jose
AU - Hayashi, Tomonori
AU - Nikolich-Žugich, Janko
N1 - Funding Information:
Supported in part by the USPHS awards AG020719 and AG048021 and the contract from the National Institute of Allergy and Infectious Diseases HHSN272200900059C, to the Radiation Effects Research Foundation (Dr Nakachi, PI) and its subcontract to Dr. Nikolich‐Zugich. The Radiation Effects Research Foundation (RERF), Hiroshima and Nagasaki, Japan, is a private, non‐profit foundation funded by the Japanese Ministry of Health, Labor and Welfare and the United States of America Department of Energy (US‐DOE), the latter in part through DOE Award DE‐HS0000031 to the US National Academy of Sciences. This study was based on RERF Research Protocol RP#4–09 and was supported by the US National Institutes of Health (NIAID Contract HHSN272200900059C). The views of the authors do not necessarily reflect those of the two governments.
Funding Information:
The authors wish to thank Drs. Michael Diamond, Wayne Yokoyama (Washington University), and Ann Hill (OHSU) for reagents and protocols. Thanks are also due to Drs. Giovanni Bosco (Dartmouth College), Ted Weinert, Kirsten Limesand, Jeff Frelinger and Mike Kuhns (University of Arizona) for critical input and suggestions. Special thanks to Dr. Wendell Lutz (Univ. of Arizona Cancer Center) for radiation dosage calibration and instruction, and Richard Wagner (University of Arizona) for help with radiation safety.
Publisher Copyright:
© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.
PY - 2022/7
Y1 - 2022/7
N2 - While whole-body irradiation (WBI) can induce some hallmarks of immune aging, (re)activation of persistent microbial infection also occurs following WBI and may contribute to immune effects of WBI over the lifespan. To test this hypothesis in a model relevant to human immune aging, we examined separate and joint effects of lifelong latent murine cytomegalovirus (MCMV) and of early-life WBI over the course of the lifespan. In late life, we then measured the response to a West Nile virus (WNV) live attenuated vaccine, and lethal WNV challenge subsequent to vaccination. We recently published that a single dose of non-lethal WBI in youth, on its own, was not sufficient to accelerate aging of the murine immune system, despite widespread DNA damage and repopulation stress in hematopoietic cells. However, 4Gy sub-lethal WBI caused manifest reactivation of MCMV. Following vaccination and challenge with WNV in the old age, MCMV-infected animals experiencing 4Gy, but not lower, dose of sub-lethal WBI in youth had reduced survival. By contrast, old irradiated mice lacking MCMV and MCMV-infected, but not irradiated, mice were both protected to the same high level as the old non-irradiated, uninfected controls. Analysis of the quality and quantity of anti-WNV immunity showed that higher mortality in MCMV-positive WBI mice correlated with increased levels of MCMV-specific immune activation during WNV challenge. Moreover, we demonstrate that infection, including that by WNV, led to MCMV reactivation. Our data suggest that MCMV reactivation may be an important determinant of increased late-life mortality following early-life irradiation and late-life acute infection.
AB - While whole-body irradiation (WBI) can induce some hallmarks of immune aging, (re)activation of persistent microbial infection also occurs following WBI and may contribute to immune effects of WBI over the lifespan. To test this hypothesis in a model relevant to human immune aging, we examined separate and joint effects of lifelong latent murine cytomegalovirus (MCMV) and of early-life WBI over the course of the lifespan. In late life, we then measured the response to a West Nile virus (WNV) live attenuated vaccine, and lethal WNV challenge subsequent to vaccination. We recently published that a single dose of non-lethal WBI in youth, on its own, was not sufficient to accelerate aging of the murine immune system, despite widespread DNA damage and repopulation stress in hematopoietic cells. However, 4Gy sub-lethal WBI caused manifest reactivation of MCMV. Following vaccination and challenge with WNV in the old age, MCMV-infected animals experiencing 4Gy, but not lower, dose of sub-lethal WBI in youth had reduced survival. By contrast, old irradiated mice lacking MCMV and MCMV-infected, but not irradiated, mice were both protected to the same high level as the old non-irradiated, uninfected controls. Analysis of the quality and quantity of anti-WNV immunity showed that higher mortality in MCMV-positive WBI mice correlated with increased levels of MCMV-specific immune activation during WNV challenge. Moreover, we demonstrate that infection, including that by WNV, led to MCMV reactivation. Our data suggest that MCMV reactivation may be an important determinant of increased late-life mortality following early-life irradiation and late-life acute infection.
KW - DNA damage
KW - T cells
KW - West Nile virus
KW - aging
KW - cytomegalovirus
KW - vaccination
UR - http://www.scopus.com/inward/record.url?scp=85131157532&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85131157532&partnerID=8YFLogxK
U2 - 10.1111/acel.13648
DO - 10.1111/acel.13648
M3 - Article
C2 - 35657768
AN - SCOPUS:85131157532
SN - 1474-9718
VL - 21
JO - Aging Cell
JF - Aging Cell
IS - 7
M1 - e13648
ER -