Elucidating kynurenine pathway control of systemic bacterial infection in macrophages

Abstract

Strategies to combat bacterial infections have focused on directly eliminating the bacteria, but a complimentary approach is to boost the host immune response. In a whole organism screen for compounds that improve survival to infection, we found that exogenous application of the kynurenine pathway metabolite 3-hydroxykynurenine (3-HK) rescued zebrafish larvae from lethal Salmonella enterica serovar Typhimurium (S. Typhimurium) bloodstream infection. Exogenous 3-HK did not act like a typical antibiotic in that it did not inhibit bacterial growth when applied directly to bacteria in axenic media but did restrict bacterial growth in vivo in a whole organism by targeting glutamate-gated kainate receptor (KAR) ion channels. We next found that kynurenine 3-monooxygenase (Kmo), the enzyme responsible for catabolism of kynurenine to 3-HK, is required for the normal innate immune response to systemic S. Typhimurium infection. Macrophages are a preferred intracellular niche for S. Typhimurium and are required for 3-HK mediated protection to infection. Transcriptional and functional assays of infected macrophages revealed that lysosomal acidification is impaired upon Kmo inhibition, which is rescued by 3-HK application as well as KAR antagonism. Taken together, this work reveals a novel role and target for 3-HK, a metabolite of the kynurenine pathway, in promoting survival to systemic Salmonella Typhimurium infection by antagonizing kainate receptors to enhance macrophage lysosomal function.