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Dryad

Bulk RNA seq of macrophages isolated from Kmo morphant or control morphant zebrafish larvae infected with Salmonella Typhimurium

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Sep 29, 2025 version files 106.98 GB

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Abstract

The kynurenine pathway of tryptophan degradation has been implicated in various diseases, including cancer, neurodegenerative disorders, and infectious diseases. A key branchpoint in this pathway is production of the metabolite 3-hydroxy-kynurenine (3-HK) by the enzyme kynurenine 3-monooxygenase (Kmo). We recently found that administration of exogenous 3-HK promotes survival to Salmonella Typhimurium infection in zebrafish larvae by restricting bacterial expansion in macrophages via a systemic mechanism that targets kainate sensitive glutamate receptor (KAR) ion channels. Here, we show that endogenous production of 3-HK by Kmo, likewise, is required for defense against systemic Salmonella Typhimurium infection in vivo and that loss of endogenous production of 3-HK impairs macrophage microbicial activity, resulting in increased bacterial expansion. Mechanistically, 3-HK acts by antagonizing KARs to promote lysosome acidification and subsequent control of bacterial burden. Finally, we establish a novel link between activity at KARs and lysosomal acidification in macrophages, revealing a novel regulatory role for KARs in promoting macrophage microbicidal activity and a novel mechanism though which 3-HK promotes control of bacterial infection.