TY - JOUR
T1 - Ketogenic diet restrains aging-induced exacerbation of coronavirus infection in mice
AU - Ryu, Seungjin
AU - Shchukina, Irina
AU - Youm, Yun Hee
AU - Qing, Hua
AU - Hilliard, Brandon
AU - Dlugos, Tamara
AU - Zhang, Xinbo
AU - Yasumoto, Yuki
AU - Booth, Carmen J.
AU - Fernández-Hernando, Carlos
AU - Suárez, Yajaira
AU - Khanna, Kamal
AU - Horvath, Tamas L.
AU - Dietrich, Marcelo O.
AU - Artyomov, Maxim
AU - Wang, Andrew
AU - Dixit, Vishwa Deep
N1 - Funding Information:
SR is supported by American Federation of Aging Research (AFAR) postdoctoral fellowship award. The Dixit lab is supported in part by NIH grants P01AG051459, AR070811 and Cure Alzheimer’s Fund. The Wang lab is supported in part by NIH grant 1K08AI128745 and by gifts from the Knights of Columbus, G Harold and Leila Y Mathers Charitable Foundation, and the Ludwig Family Foundation. We also thank the Yale Center on Genomic Analysis (YCGA) for RNA-seq studies and Genen-tech Inc for providing the anti-caspase-1 antibody.
Funding Information:
SR is supported by American Federation of Aging Research (AFAR) postdoctoral fellowship award. The Dixit lab is supported in part by NIH grants P01AG051459, AR070811 and Cure Alzheimer?s Fund. The Wang lab is supported in part by NIH grant 1K08AI128745 and by gifts from the Knights of Columbus, G Harold and Leila Y Mathers Charitable Foundation, and the Ludwig Family Foundation. We also thank the Yale Center on Genomic Analysis (YCGA) for RNA-seq studies and Genentech Inc for providing the anti-caspase-1 antibody.
Publisher Copyright:
© Ryu et al.
PY - 2021/6
Y1 - 2021/6
N2 - Increasing age is the strongest predictor of risk of COVID-19 severity and mortality. Immunometabolic switch from glycolysis to ketolysis protects against inflammatory damage and influenza infection in adults. To investigate how age compromises defense against coronavirus infection, and whether a pro-longevity ketogenic diet (KD) impacts immune surveillance, we developed an aging model of natural murine beta coronavirus (mCoV) infection with mouse hepatitis virus strain-A59 (MHV-A59). When inoculated intranasally, mCoV is pneumotropic and recapitulates several clinical hallmarks of COVID-19 infection. Aged mCoV-A59-infected mice have increased mortality and higher systemic inflammation in the heart, adipose tissue, and hypothalamus, including neutrophilia and loss of gd T cells in lungs. Activation of ketogenesis in aged mice expands tissue protective gd T cells, deactivates the NLRP3 inflammasome, and decreases pathogenic monocytes in lungs of infected aged mice. These data establish harnessing of the ketogenic immunometabolic checkpoint as a potential treatment against coronavirus infection in the aged.
AB - Increasing age is the strongest predictor of risk of COVID-19 severity and mortality. Immunometabolic switch from glycolysis to ketolysis protects against inflammatory damage and influenza infection in adults. To investigate how age compromises defense against coronavirus infection, and whether a pro-longevity ketogenic diet (KD) impacts immune surveillance, we developed an aging model of natural murine beta coronavirus (mCoV) infection with mouse hepatitis virus strain-A59 (MHV-A59). When inoculated intranasally, mCoV is pneumotropic and recapitulates several clinical hallmarks of COVID-19 infection. Aged mCoV-A59-infected mice have increased mortality and higher systemic inflammation in the heart, adipose tissue, and hypothalamus, including neutrophilia and loss of gd T cells in lungs. Activation of ketogenesis in aged mice expands tissue protective gd T cells, deactivates the NLRP3 inflammasome, and decreases pathogenic monocytes in lungs of infected aged mice. These data establish harnessing of the ketogenic immunometabolic checkpoint as a potential treatment against coronavirus infection in the aged.
UR - http://www.scopus.com/inward/record.url?scp=85108893605&partnerID=8YFLogxK
U2 - 10.7554/eLife.66522
DO - 10.7554/eLife.66522
M3 - Article
C2 - 34151773
AN - SCOPUS:85108893605
SN - 2050-084X
VL - 10
JO - eLife
JF - eLife
M1 - e66522
ER -