{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T11:33:35Z","timestamp":1774611215995,"version":"3.50.1"},"posted":{"date-parts":[[2020,9,12]]},"group-title":"Immunology","reference-count":63,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2020,9,12]],"date-time":"2020-09-12T00:00:00Z","timestamp":1599868800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2020,9,12]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>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 \u03b3\u03b4 T cells in lungs. Ketogenic diet increases beta-hydroxybutyrate, expands tissue protective \u03b3\u03b4 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.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:p>\n                    <jats:list list-type=\"simple\">\n                      <jats:list-item>\n                        <jats:label>-<\/jats:label>\n                        <jats:p>Natural MHV-A59 mouse coronavirus infection mimics COVID-19 in elderly.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:label>-<\/jats:label>\n                        <jats:p>Aged infected mice have systemic inflammation and inflammasome activation<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:label>-<\/jats:label>\n                        <jats:p>Murine beta coronavirus (mCoV) infection results in loss of pulmonary \u03b3\u03b4 T cells.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:label>-<\/jats:label>\n                        <jats:p>Ketones protect aged mice from infection by reducing inflammation.<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>eTOC Blurb<\/jats:title>\n                  <jats:p>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 \u03b3\u03b4 T cells that was corrected by ketogenic diet.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2020.09.11.294363","type":"posted-content","created":{"date-parts":[[2020,9,13]],"date-time":"2020-09-13T01:15:15Z","timestamp":1599959715000},"source":"Crossref","is-referenced-by-count":5,"title":["Ketogenesis restrains aging-induced exacerbation of COVID in a mouse model"],"prefix":"10.64898","author":[{"given":"Seungjin","family":"Ryu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irina","family":"Shchukina","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yun-Hee","family":"Youm","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hua","family":"Qing","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brandon K.","family":"Hilliard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tamara","family":"Dlugos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinbo","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuki","family":"Yasumoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carmen J.","family":"Booth","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos","family":"Fern\u00e1ndez-Hernando","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yajaira","family":"Su\u00e1rez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kamal M.","family":"Khanna","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tamas L.","family":"Horvath","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcelo O.","family":"Dietrich","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maxim N.","family":"Artyomov","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vishwa Deep","family":"Dixit","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024080415473606000_2020.09.11.294363v1.1","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1038\/s41564-019-0371-3","article-title":"Dampened NLRP3-mediated inflammation in bats and implications for a special viral reservoir host","volume":"4","year":"2019","journal-title":"Nature Microbiology"},{"key":"2024080415473606000_2020.09.11.294363v1.2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abb0762"},{"key":"2024080415473606000_2020.09.11.294363v1.3","doi-asserted-by":"publisher","DOI":"10.1101\/002824"},{"key":"2024080415473606000_2020.09.11.294363v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0266-9"},{"key":"2024080415473606000_2020.09.11.294363v1.5","doi-asserted-by":"crossref","unstructured":"Bauernfeind, F. , Niepmann, S. , Knolle, P.A. , and Hornung, V. 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