Department of Molecular Biology and Center for Computational and Integrative Biology, Massachusetts General Hospital (MGH), Boston, MA, USA.
Department of Genetics, Harvard Medical School, Boston, MA, USA.
Nat Chem Biol. 2024 Dec;20(12):1586-1596. doi: 10.1038/s41589-024-01635-z. Epub 2024 Jun 19.
Bacterial infection involves a complex interaction between the pathogen and host where the outcome of infection is not solely determined by pathogen eradication. To identify small molecules that promote host survival by altering the host-pathogen dynamic, we conducted an in vivo chemical screen using zebrafish embryos and found that treatment with 3-hydroxykynurenine (3-HK) protects from lethal bacterial infection. 3-HK, a metabolite produced through host tryptophan metabolism, has no direct antibacterial activity but enhances host survival by restricting bacterial expansion in macrophages through a systemic mechanism that targets kainate-sensitive glutamate receptors. These findings reveal a new pathway by which tryptophan metabolism and kainate-sensitive glutamate receptors function and interact to modulate immunity, with important implications for the coordination between the immune and nervous systems in pathological conditions.
细菌感染涉及病原体和宿主之间的复杂相互作用，感染的结果不仅仅取决于病原体的清除。为了通过改变宿主-病原体动态来识别促进宿主存活的小分子，我们使用斑马鱼胚胎进行了体内化学筛选，发现 3-羟基犬尿氨酸（3-HK）的处理可防止致命的细菌感染。3-HK 是宿主色氨酸代谢产生的一种代谢物，没有直接的抗菌活性，但通过一种系统性机制通过靶向 kainate 敏感型谷氨酸受体来限制巨噬细胞中细菌的扩张，从而增强宿主的存活。这些发现揭示了色氨酸代谢和 kainate 敏感型谷氨酸受体发挥作用并相互作用以调节免疫的新途径，这对病理条件下免疫系统和神经系统之间的协调具有重要意义。
