Kmo restricts Salmonella in a whole organism infection model by promoting macrophage lysosomal acidification through kainate receptor antagonism.

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 have previously reported that administration of exogenous 3-HK promotes survival of zebrafish larvae to Salmonella Typhimurium infection by restricting bacterial expansion via a systemic mechanism that targets kainate sensitive glutamate receptor (KAR) ion channels and that the endogenous production of 3-HK by Kmo is required for defense against systemic Salmonella infection. Here we show that endogenous 3-HK promotes lysosomal acidification to contribute to macrophage microbicidal activity, with its absence leading to increased host susceptibility to infection. Further, 3-HK promotes lysosomal acidification in a KAR-dependent manner. We thus reveal a novel link between KARs and macrophage lysosomal acidification, and a novel mechanism by which 3-HK promotes control of bacterial infection. Author SummaryStandard therapy for bacterial infections involves antibiotics to clear pathogens. However, the host immune system can also efficiently eliminate bacteria. We have recently shown that a metabolite of the kynurenine metabolic pathway, 3-hydroxy-kynurenine (3-HK), plays a role in the innate immune response to bacterial infection. Here, we show that the kynurenine pathway promotes macrophage clearance of intracellular bacteria by increasing lysosomal acidification of engulfed bacteria and that 3-HK does so by antagonizing kainate receptors. Together, this adds to our understanding of how multiple biological systems, including metabolic and immune pathways, interact to boost defense against bacteria.