Ketogenic diet restrains aging-induced exacerbation of coronavirus infection in mice

eLife

Xinbo Zhang¹  Carmen J Booth¹  Yuki Yasumoto¹  Seungjin Ryu²  Yun-Hee Youm²  Tamara Dlugos²  Vishwa Deep Dixit³  Carlos Fernández-Hernando⁴  Yajaira Suárez⁴  Marcelo O Dietrich⁴  Tamas L Horvath⁵  Andrew Wang⁶  Brandon Hilliard⁷  Hua Qing⁷  Kamal Khanna⁸  Maxim Artyomov⁹  Irina Shchukina⁹ 

[1] Department of Comparative Medicine, Yale School of Medicine, New Haven, United States;Department of Comparative Medicine, Yale School of Medicine, New Haven, United States;Department of Immunobiology, Yale School of Medicine, New Haven, United States;Department of Comparative Medicine, Yale School of Medicine, New Haven, United States;Department of Immunobiology, Yale School of Medicine, New Haven, United States;Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale School of Medicine, New Haven, United States;Yale Center for Research on Aging, New Haven, United States;Department of Comparative Medicine, Yale School of Medicine, New Haven, United States;Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale School of Medicine, New Haven, United States;Department of Comparative Medicine, Yale School of Medicine, New Haven, United States;Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale School of Medicine, New Haven, United States;Yale Center for Research on Aging, New Haven, United States;Department of Immunobiology, Yale School of Medicine, New Haven, United States;Department of Internal Medicine, Yale School of Medicine, New Haven, United States;Department of Internal Medicine, Yale School of Medicine, New Haven, United States;Department of Microbiology, New York University Langone Health, New York, United States;Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States;

关键词: aging;    MHV;    coronavirus;    inflammasome;    gamma delta t cell;    ketogenic diet;    Mouse;   

DOI  :  10.7554/eLife.66522

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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 γδ T cells in lungs. Activation of ketogenesis in aged mice expands tissue protective γδ 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.

【 授权许可】

CC BY