Ketogenic diet restrains aging-induced exacerbation of coronavirus infection in mice
- Yale University, United States
- Washington University School of Medicine, United States
- Yale University School of Medicine, United States
- New York University Langone Health, United States
- Yale School of Medicine, United States
Abstract
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.
Data availability
The single cell RNA-sequencing and bulk RNA-sequencing data has been uploaded to Gene Expression Omnibus (GSE155346 and GSE155347) respectively.
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Ketogenesis restrains aging-induced exacerbation of COVID in a mouse modelNCBI Gene Expression Omnibus, GSE155346.
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Ketogenesis restrains aging-induced exacerbation of COVID in a mouse modelNCBI Gene Expression Omnibus, GSE155347.
Article and author information
Author details
Marcelo O Dietrich
Funding
National Institute on Aging (P01AG051459)
- Vishwa Deep Dixit
National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR070811)
- Vishwa Deep Dixit
American Federation for Aging Research (Glenn Foundation for Medical Research Postdoctoral Fellowships in Aging Research)
- Seungjin Ryu
National Institute of Allergy and Infectious Diseases (1K08AI128745)
- Andrew Wang
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Chyung-Ru Wang, Northwestern University, United States
Ethics
Animal experimentation: All experiments and animal use were conducted in compliance with the National Institute of Health Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee (IACUC) protocol (#2019-11572 and 2020-20149) of Yale University.
Version history
- Received: January 13, 2021
- Accepted: June 15, 2021
- Accepted Manuscript published: June 21, 2021 (version 1)
- Version of Record published: June 30, 2021 (version 2)
Copyright
© 2021, Ryu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Ketogenic diet restrains aging-induced exacerbation of coronavirus infection in mice
eLife 10:e66522.
https://doi.org/10.7554/eLife.66522
Further reading
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CD4+ T cell activation is driven by five-module receptor complexes. The T cell receptor (TCR) is the receptor module that binds composite surfaces of peptide antigens embedded within MHCII molecules (pMHCII). It associates with three signaling modules (CD3γε, CD3δε, and CD3ζζ) to form TCR-CD3 complexes. CD4 is the coreceptor module. It reciprocally associates with TCR-CD3-pMHCII assemblies on the outside of a CD4+ T cells and with the Src kinase, LCK, on the inside. Previously, we reported that the CD4 transmembrane GGXXG and cytoplasmic juxtamembrane (C/F)CV+C motifs found in eutherian (placental mammal) CD4 have constituent residues that evolved under purifying selection (Lee et al., 2022). Expressing mutants of these motifs together in T cell hybridomas increased CD4-LCK association but reduced CD3ζ, ZAP70, and PLCγ1 phosphorylation levels, as well as IL-2 production, in response to agonist pMHCII. Because these mutants preferentially localized CD4-LCK pairs to non-raft membrane fractions, one explanation for our results was that they impaired proximal signaling by sequestering LCK away from TCR-CD3. An alternative hypothesis is that the mutations directly impacted signaling because the motifs normally play an LCK-independent role in signaling. The goal of this study was to discriminate between these possibilities. Using T cell hybridomas, our results indicate that: intracellular CD4-LCK interactions are not necessary for pMHCII-specific signal initiation; the GGXXG and (C/F)CV+C motifs are key determinants of CD4-mediated pMHCII-specific signal amplification; the GGXXG and (C/F)CV+C motifs exert their functions independently of direct CD4-LCK association. These data provide a mechanistic explanation for why residues within these motifs are under purifying selection in jawed vertebrates. The results are also important to consider for biomimetic engineering of synthetic receptors.
