Ketogenesis restrains aging-induced exacerbation of COVID in 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

doi: https://doi.org/10.1101/2020.09.11.294363

This article is a preprint and has not been certified by peer review [what does this mean?].

PDF: https://www.biorxiv.org/content/10.1101/2020.09.11.294363v1.full.pdf

SUMMARY

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.

• - 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.

Competing Interest Statement

The authors have declared no competing interest.

https://www.biorxiv.org/content/10.1101/2020.09.11.294363v1