{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T14:19:44Z","timestamp":1788790784050,"version":"build-2803163510"},"reference-count":113,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003141","name":"Secretar\u00eda de Ciencia, Humanidades, Tecnolog\u00eda e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["CBF-2025-I-1331"],"award-info":[{"award-number":["CBF-2025-I-1331"]}],"id":[{"id":"10.13039\/501100003141","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004881","name":"Instituto Mexicano del Seguro Social","doi-asserted-by":"publisher","award":["R-2024-785-073"],"award-info":[{"award-number":["R-2024-785-073"]}],"id":[{"id":"10.13039\/501100004881","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>RNA virus infections are shaped by the interplay among viral replication, innate immune sensing, and host metabolism, which together determine the magnitude, duration, and quality of antiviral responses. The tryptophan\u2013kynurenine (Trp\u2013Kyn) pathway has emerged as an important immunometabolic axis linking interferon-driven inflammation, amino acid availability, immune-cell function, tissue homeostasis, and viral persistence. This review examines the roles of indoleamine 2,3-dioxygenase 1 (IDO1), IDO2, tryptophan 2,3-dioxygenase (TDO), Trp depletion, general control nonderepressible 2 (GCN2) signaling, mechanistic target of rapamycin complex 1 (mTORC1), Kyn-derived metabolites, and aryl hydrocarbon receptor (AhR) activation in host responses to RNA virus infection. We integrate genetic, pharmacological, cellular, animal, and clinical evidence across positive-sense and negative-sense single-stranded RNA viruses, double-stranded RNA viruses, and reverse-transcribing RNA viruses, including SARS-CoV-2, dengue virus, Zika virus, hepatitis C virus, influenza A virus, respiratory syncytial virus, rotavirus, reovirus, HIV-1, and SIV. Across these systems, the Trp\u2013Kyn\u2013AhR axis can influence interferon responses, viral replication, immune-cell function, tissue injury, and disease outcome. EMCV myocarditis provides causal proof of principle, whereas other RNA-virus models provide complementary functional and clinical evidence. Importantly, pathway activation does not confer a uniform antiviral or pathogenic phenotype; its biological consequences depend on viral class, tissue tropism, viral burden, inflammatory intensity, cell type, and disease stage. On this basis, we propose a time-phase model in which early or excessive IDO1\u2013Kyn\u2013AhR signaling may impair type I interferon responses, NK-cell function, CD8+ T-cell expansion, and viral clearance, whereas appropriately regulated activation during later inflammatory or resolution phases may limit immunopathology, support epithelial repair, and preserve tissue homeostasis. Persistent or dysregulated activation may instead contribute to exhaustion-like immune states, chronic inflammation, neuroimmune dysfunction, and post-acute viral sequelae. Finally, we discuss phase-adapted therapeutic strategies, including IDO1 inhibition, AhR agonism or antagonism, KMO-directed modulation, Trp-based entry inhibitors, and biomarker-guided combination approaches. Together, these findings position the Trp\u2013Kyn\u2013AhR axis as a dynamic, context-dependent target for precision host-directed antiviral immunometabolism.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1923351","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T13:22:48Z","timestamp":1788787368000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The kynurenine pathway in RNA virus infection: immunometabolic control of antiviral defense and viral persistence"],"prefix":"10.3389","volume":"17","author":[{"given":"Daniela Nahomi","family":"Calder\u00f3n-Sandate","sequence":"first","affiliation":[{"name":"Laboratorio de Virolog\u00eda Molecular, Unidad de Investigaci\u00f3n Biom\u00e9dica de Zacatecas, Instituto Mexicano del Seguro Social","place":["Zacatecas, Mexico"]},{"name":"Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies of the National Polytechnic Institute","place":["Mexico City, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel Josafat","family":"Huerta-Garza","sequence":"additional","affiliation":[{"name":"Laboratorio de Virolog\u00eda Molecular, Unidad de Investigaci\u00f3n Biom\u00e9dica de Zacatecas, Instituto Mexicano del Seguro Social","place":["Zacatecas, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blanca Azucena","family":"M\u00e1rquez-Reyna","sequence":"additional","affiliation":[{"name":"Laboratorio de Virolog\u00eda Molecular, Unidad de Investigaci\u00f3n Biom\u00e9dica de Zacatecas, Instituto Mexicano del Seguro Social","place":["Zacatecas, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David Mauricio","family":"Ca\u00f1edo-Figueroa","sequence":"additional","affiliation":[{"name":"Laboratorio de Virolog\u00eda Molecular, Unidad de Investigaci\u00f3n Biom\u00e9dica de Zacatecas, Instituto Mexicano del Seguro 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