沙门氏菌通过调节巨噬细胞糖代谢增强在细胞内复制和致病性的机制研究

致病菌和宿主细胞的相互作用与疾病发展密切相关。沙门氏菌是一种重要的人类致病菌，能引起肠炎和系统性疾病。在巨噬细胞内复制是沙门氏菌引起系统性感染的关键步骤。然而，沙门氏菌如何与巨噬细胞在代谢水平上相互作用以促进其胞内复制尚不清楚。在前期工作中，我们发现沙门氏菌感染后能特异性诱导巨噬细胞糖代谢的改变，在提高巨噬细胞糖酵解水平的同时降低糖酵解中间产物合成丝氨酸的水平，造成细胞内糖酵解中间产物的积累，并证实这种代谢方式有利于沙门氏菌在巨噬细胞内的复制和致病性。本研究在前期工作基础上，拟结合多组学分析技术和多种分子生物学实验技术，进一步探究相关的分子机制。包括两个方面：第一，揭示有利于沙门氏菌复制的巨噬细胞糖酵解中间产物，阐明与中间产物转运相关的调节网络；第二，揭示沙门氏菌抑制巨噬细胞丝氨酸合成途径的分子机制。研究结果对于全面理解沙门氏菌的致病机理及其与宿主的相互作用机制具有重要意义。

Host-pathogen interactions are closely related to disease development. Salmonella is an important intracellular pathogen, causing gastroenteritis and systemic disease in humans. Salmonella survival and replication in macrophages is essential for the establishment of systemic disease in the host. However, how Salmonella interacts with macrophages at metabolic levels to promote its intracellular replication is unclear. In our preliminary work, we found that Salmonella can specifically modulate macrophage glucose metabolism, by up-regulating glycolysis and, at the same time, down-regulating the synthesis of serine from glycolytic intermediate 3-phosphoglycerate, resulting in the accumulation of glycolytic intermediates in the infected macrophages. We further confirmed that this Salmonella-driven macrophage metabolic reprogram contributes to Salmonella intracellular replication and systemic infection. This work will further investigate the underlying mechanisms, using multiple molecular techniques, from the following two aspects. First, to investigate which glycolytic intermediates contribute to Salmonella intracellular replication, and the regulatory network related to the uptake of these glycolytic intermediates. Second, to investigate the mechanism utilized by Salmonella to repress macrophage serine synthesis pathway. This work will significantly enhance our understanding on the pathogenesis of Salmonella and the mechanisms of Salmonella-host interactions.