Parada-Kusz Margarita, Clatworthy Anne E, Goering Emily R, Blackwood Stephanie M, Salm Elizabeth J, Choi Catherine, Combs Senya, Lee Jenny S W, Rodriguez-Osorio Carlos, Tomita Susumu, Hung Deborah T
Department of Molecular Biology and Center for Computational and Integrative Biology, Massachusetts General Hospital; Boston, Massachusetts, USA.
Department of Genetics, Harvard Medical School; Boston, Massachusetts, USA.
bioRxiv. 2023 Aug 18:2023.08.16.553532. doi: 10.1101/2023.08.16.553532.
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 chemical screen using zebrafish embryos and found that treatment with 3-hydroxy-kynurenine protects from lethal gram-negative bacterial infection. 3-hydroxy-kynurenine, a metabolite produced through host tryptophan metabolism, has no direct antibacterial activity but enhances host survival by restricting bacterial expansion in macrophages by targeting kainate-sensitive glutamate receptors. These findings reveal new mechanisms by which tryptophan metabolism and kainate-sensitive glutamate receptors function and interact to modulate immunity, with significant implications for the coordination between the immune and nervous systems in pathological conditions.
细菌感染涉及病原体与宿主之间复杂的相互作用，感染的结果并非仅由病原体的根除来决定。为了识别通过改变宿主-病原体动态来促进宿主存活的小分子，我们利用斑马鱼胚胎进行了化学筛选，发现用3-羟基犬尿氨酸处理可保护机体免受致命的革兰氏阴性细菌感染。3-羟基犬尿氨酸是宿主色氨酸代谢产生的一种代谢产物，没有直接的抗菌活性，但通过靶向对红藻氨酸敏感的谷氨酸受体来限制巨噬细胞内细菌的增殖，从而提高宿主的存活率。这些发现揭示了色氨酸代谢和对红藻氨酸敏感的谷氨酸受体发挥功能并相互作用以调节免疫的新机制，对病理状态下免疫和神经系统之间的协调具有重要意义。
