Ketogenesis restrains aging-induced exacerbation of COVID in a mouse model
Seungjin Ryu, Irina Shchukina, Yun-Hee Youm, Hua Qing, Brandon K Hilliard, Tamara Dlugos, Xinbo Zhang, Yuki Yasumoto, Carmen J Booth, Carlos Fernández-Hernando, Yajaira Suárez, Kamal M Khanna, Tamas L Horvath, Marcelo O Dietrich, Maxim N Artyomov, Andrew Wang, Vishwa Deep Dixit, Seungjin Ryu, Irina Shchukina, Yun-Hee Youm, Hua Qing, Brandon K Hilliard, Tamara Dlugos, Xinbo Zhang, Yuki Yasumoto, Carmen J Booth, Carlos Fernández-Hernando, Yajaira Suárez, Kamal M Khanna, Tamas L Horvath, Marcelo O Dietrich, Maxim N Artyomov, Andrew Wang, Vishwa Deep Dixit
Abstract
Increasing age is the strongest predictor of risk of COVID-19 severity. Unregulated cytokine storm together with impaired immunometabolic response leads to highest mortality in elderly infected with SARS-CoV-2. To investigate how aging compromises defense against COVID-19, we developed a model of natural murine beta coronavirus (mCoV) infection with mouse hepatitis virus strain MHV-A59 (mCoV-A59) that recapitulated majority of clinical hallmarks of COVID-19. 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. Ketogenic diet increases beta-hydroxybutyrate, expands tissue protective γδ T cells, deactivates the inflammasome and decreases pathogenic monocytes in lungs of infected aged mice. These data underscore the value of mCoV-A59 model to test mechanism and establishes harnessing of the ketogenic immunometabolic checkpoint as a potential treatment against COVID-19 in the elderly.
Highlights: - Natural MHV-A59 mouse coronavirus infection mimics COVID-19 in elderly.- Aged infected mice have systemic inflammation and inflammasome activation.- Murine beta coronavirus (mCoV) infection results in loss of pulmonary γδ T cells.- Ketones protect aged mice from infection by reducing inflammation.
Etoc blurb: Elderly have the greatest risk of death from COVID-19. Here, Ryu et al report an aging mouse model of coronavirus infection that recapitulates clinical hallmarks of COVID-19 seen in elderly. The increased severity of infection in aged animals involved increased inflammasome activation and loss of γδ T cells that was corrected by ketogenic diet.
Source: PubMed