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However, the metabolic mechanisms that govern these divergent roles remain poorly understood, limiting opportunities for therapeutic intervention. Single\u2010cell RNA\u2010sequencing and metabolic flow analysis of brain and bone marrow (BM) is used to map the metabolic signatures of monocyte\u2010derived cells (MCs) during lethal West Nile virus encephalitis. Trajectory analysis shows that BM monocytes progress through three metabolic profiles before migrating to the brain and differentiating into a pro\u2010inflammatory HIF1\u2010\u03b1\u207a MC population. This population further diverges into an inflammatory, iNOS\u207a MC subset with high glycolysis and amino acid metabolism, and a protective, glycolytically quiescent, antigen\u2010presenting MC subset. Daily in vivo glycolysis inhibition reduces neuroinflammation and disease signs without increasing viral load. This effect does not reflect a broad reduction in myelopoiesis but rather a selective decrease in iNOS\u207a MC migration, revealing distinct glycolytic dependencies among MC subsets. HIF1\u2010\u03b1 activity remains independent of glycolysis, enabling functional differentiation of antigen\u2010presenting MCs without impairing antiviral responses by cervical lymph node T cells. This study identifies key metabolic drivers of MC function in viral CNS disease, in which selective metabolic reprogramming reduces severe neuroinflammation, demonstrating a promising therapeutic strategy.<\/jats:p>","DOI":"10.1002\/advs.202505844","type":"journal-article","created":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T11:56:06Z","timestamp":1752494166000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Metabolic Programming Drives Protective and Inflammatory Monocyte Fates in Viral Encephalitis"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4299-159X","authenticated-orcid":false,"given":"Claire L.","family":"Wishart","sequence":"first","affiliation":[{"name":"Infection, Immunity, Inflammation Research Theme School of Medical Sciences Faculty of Medicine and Health The University of Sydney  Sydney NSW NSW 2006 Australia"},{"name":"Charles Perkins Centre The University of Sydney  Sydney NSW NSW 2006 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6787-6195","authenticated-orcid":false,"given":"Alanna G.","family":"Spiteri","sequence":"additional","affiliation":[{"name":"Infection, Immunity, Inflammation Research Theme School of Medical Sciences Faculty of Medicine and Health The University of Sydney  Sydney NSW NSW 2006 Australia"},{"name":"Charles Perkins Centre The University of Sydney  Sydney NSW NSW 2006 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1359-1797","authenticated-orcid":false,"given":"Jian","family":"Tan","sequence":"additional","affiliation":[{"name":"Infection, Immunity, Inflammation Research Theme School of Medical Sciences Faculty of Medicine and Health The University of Sydney  Sydney NSW NSW 2006 Australia"},{"name":"Chronic Diseases Research Theme School of Medical Sciences Faculty of Medicine and Health The University of Sydney  Sydney NSW NSW 2006 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0835-851X","authenticated-orcid":false,"given":"Laurence","family":"Macia","sequence":"additional","affiliation":[{"name":"Infection, Immunity, Inflammation Research Theme School of Medical Sciences Faculty of Medicine and Health The University of Sydney  Sydney NSW NSW 2006 Australia"},{"name":"Chronic Diseases Research Theme School of Medical Sciences Faculty of Medicine and Health The University of Sydney  Sydney NSW NSW 2006 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3877-9772","authenticated-orcid":false,"given":"Nicholas J. 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