{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T12:33:24Z","timestamp":1762432404277,"version":"3.37.3"},"reference-count":54,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T00:00:00Z","timestamp":1736208000000},"content-version":"vor","delay-in-days":556,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Dysregulation of host metabolism is a feature of lethal SARS-CoV-2 infection. Perturbations in \u03b1-ketoglutarate levels can elicit metabolic reprogramming through 2-oxoglutarate\u2013dependent dioxygenases (2-ODDGs), leading to stabilization of the transcription factor HIF-1\u03b1. HIF1-\u03b1 activation has been reported to promote antiviral mechanisms against SARS-CoV-2 through direct regulation of ACE2 expression (a receptor required for viral entry). However, given the numerous pathways HIF-1\u03b1 serves to regulate it is possible that there are other undefined metabolic mechanisms contributing to the pathogenesis of SARS-CoV-2 independent of ACE2 downregulation. In this study, we used in vitro and in vivo models in which HIF-1\u03b1 modulation of ACE2 expression was negated, allowing for isolated characterization of the host metabolic response within SARS-CoV-2 disease pathogenesis. We demonstrated that SARS-CoV-2 infection limited stabilization of HIF-1\u03b1 and associated mitochondrial metabolic reprogramming by maintaining activity of the 2-ODDG prolyl hydroxylases. Inhibition of 2-ODDGs with dimethyloxalylglycine promoted HIF-1\u03b1 stabilization following SARS-CoV-2 infection, and significantly increased survival among SARS-CoV-2\u2013infected mice compared with vehicle controls. However, unlike previous reports, the mechanism by which activation of HIF-1\u03b1 responses contributed to survival was not through impairment of viral replication. Rather, dimethyloxalylglycine treatment facilitated direct effects on host metabolism including increased glycolysis and resolution of dysregulated pools of metabolites, which correlated with reduced morbidity. Taken together, these data identify (to our knowledge) a novel function of \u03b1-ketoglutarate\u2013sensing platforms, including those responsible for HIF-1\u03b1 stabilization, in the resolution of SARS-CoV-2 infection and support targeting these metabolic nodes as a viable therapeutic strategy to limit disease severity during infection.<\/jats:p>","DOI":"10.4049\/immunohorizons.2300048","type":"journal-article","created":{"date-parts":[[2023,7,7]],"date-time":"2023-07-07T13:36:07Z","timestamp":1688736967000},"page":"528-542","source":"Crossref","is-referenced-by-count":1,"title":["Targeting 2-Oxoglutarate\u2013Dependent Dioxygenases Promotes Metabolic Reprogramming That Protects against Lethal SARS-CoV-2 Infection in the K18-hACE2 Transgenic Mouse Model"],"prefix":"10.1093","volume":"7","author":[{"given":"Forrest","family":"Jessop","sequence":"first","affiliation":[{"name":"Immunity to Pulmonary Pathogens Section, Laboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Disease , Hamilton, MT"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5894-953X","authenticated-orcid":false,"given":"Benjamin","family":"Schwarz","sequence":"additional","affiliation":[{"name":"Immunity to Pulmonary Pathogens Section, Laboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Disease , Hamilton, MT"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Bohrnsen","sequence":"additional","affiliation":[{"name":"Immunity to Pulmonary Pathogens Section, Laboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Disease , Hamilton, MT"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Molly","family":"Miltko","sequence":"additional","affiliation":[{"name":"Immunity to Pulmonary Pathogens Section, Laboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Disease , Hamilton, MT"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8907-8821","authenticated-orcid":false,"given":"Carl","family":"Shaia","sequence":"additional","affiliation":[{"name":"Rocky Mountain Veterinary Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Disease , Hamilton, MT"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catharine M","family":"Bosio","sequence":"additional","affiliation":[{"name":"Immunity to Pulmonary Pathogens Section, Laboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Disease , Hamilton, MT"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2023,7,7]]},"reference":[{"key":"2025010703562550200_r1","doi-asserted-by":"crossref","first-page":"838","DOI":"10.3390\/jpm11090838","article-title":"Long COVID-19 pulmonary sequelae and management considerations","volume":"11","author":"Boutou","year":"2021","journal-title":"J. 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