Mechanisms of persistent Salmonella infection

 描述(由申请人提供)：我们研究了沙门氏菌与宿主的相互作用，并表明脂肪酸代谢的宿主调节剂PPARδ可以控制小鼠持续的系统性鼠伤寒沙门氏菌感染。PPARδ是一种转录因子，在调节代谢和免疫途径中发挥作用，在沙门氏菌感染的巨噬细胞中特异性上调。重要的是，PPARδ缺陷小鼠不会慢性感染鼠伤寒沙门氏菌。这项研究提案的长期目标是了解鼠伤寒沙门氏菌在慢性感染期间如何篡夺和操纵宿主的代谢和免疫活动。在目标1中，我们将使用遗传和生化方法来确定依赖沙门氏菌激活PPARδ的机制。在目标2中，我们将确定沙门氏菌在巨噬细胞中复制所需的依赖PPARδ的免疫和代谢途径。在目标3中，我们将使用无菌小鼠和巨噬细胞或肠道上皮细胞中PPARδ缺乏的小鼠来表征PPARδ依赖的沙门氏菌在胃肠道中持续存在的机制。这些研究旨在更好地了解慢性感染过程中宿主与病原体相互作用的分子机制，从而指导合理设计有利于公众健康的治疗方法。

 DESCRIPTION (provided by applicant): We study Salmonella-host interactions and have shown that a host regulator of fatty acid metabolism, PPARδ, controls persistent systemic S. Typhimurium infection in mice. PPARδ, a transcriptional factor that plays a role in regulating metabolic and immune pathways, is specifically upregulated in Salmonella- infected macrophages. Importantly, PPARδ-deficient mice are not chronically infected with S. Typhimurium. The long-term goal of this research proposal is to understand how S. Typhimurium usurps and manipulates host metabolic and immune activities during chronic infection. In Aim 1, we will use genetic and biochemical approaches to identify mechanisms of Salmonella-dependent activation of PPARδ. In Aim 2, we will identify the PPARδ-dependent immune and metabolic pathways required for Salmonella replication in macrophages. In Aim 3, we will use germ-free mice and mice deficient for PPARδ in macrophages or gut epithelial cells to characterize PPARδ-dependent mechanisms of Salmonella persistence in the gastrointestinal tract. These studies are aimed at gaining a better understanding of the molecular mechanisms of host-pathogen interactions during chronic infections, which will lead to the rational design of therapeutics that will benefit public health.