Mechanisms of methylthioadenosine signaling during Salmonella infection

项目摘要/摘要： 鼠伤寒沙门氏菌是引起胃肠炎和非霍乱弧菌的主要原因。 世界范围内的伤寒菌血症。我们实验室之前的工作已经证明，代谢物， 甲硫腺苷(MTA)能够模式化宿主对鼠伤寒沙门氏菌的反应。我最近的作品 证实了该分子在鼠伤寒沙门氏菌入侵过程中发挥第二作用，其中MTA直接 通过抑制沙门氏菌致病岛-1和鞭毛抑制鼠伤寒沙门氏菌的毒力 正规药。这反过来又抑制了细菌入侵肠道细胞、引发炎症和 导致体内毒力降低。虽然我最近的出版物描述了这种现象，但这种机制是通过 目前尚不清楚哪种MTA能被鼠伤寒沙门氏菌感知并抑制细菌毒力。此外，虽然 我们已经描述了在沙门氏菌感染期间血清中MTA浓度的变化，我们没有 先前探索了这种代谢物在肠道中的浓度在自然过程中变化的可能性 沙门氏菌感染模型。如果在感染期间代谢物在肠道中以不同的浓度存在，它 目前尚不清楚这些浓度的变化是否会对细菌成功 把肠子变成殖民地。这项提议将解决我的假设，即宿主MTA可以影响疾病结果 通过在感染期间抑制鼠伤寒沙门氏菌的毒力。这将是一个新的宿主的例子- 病原体串扰影响肠道感染结果。 这项资助的目的是发展对鼠伤寒沙门氏菌如何感知和 对MTA的反应，并探索这种感知对感染期间宿主-病原体串扰的影响。 为了解决这个问题，我将测量小鼠肠道中MTA的空间和时间调节，并测试 宿主产生的MTA在体内抑制鼠伤寒沙门氏菌的毒力。然后我将配对蛋白质组，基因组，和 转录学方法阐明MTA介导的抑制S。 鼠伤寒杆菌毒力。总而言之，这些发现将为该项目的长期目标提供信息--即 了解如何利用操纵宿主和/或细菌蛋氨酸代谢来改善 沙门氏菌感染结果。

Project Summary/Abstract: Salmonella enterica serovar Typhimurium (S. Typhimurium) is a leading cause of gastroenteritis and non- typhoidal bacteremia worldwide. Previous work from our lab has demonstrated that the metabolite, methylthioadenosine (MTA), is able to module the host response to S. Typhimurium. My recent work demonstrated that the molecule serves a second role during S. Typhimurium invasion in which MTA directly suppresses S. Typhimurium virulence by repressing the Salmonella Pathogenicity Island-1 and the flagella regulon. This in turn suppresses the ability for the bacteria to invade cells in the gut, induce inflammation, and results in reduced in vivo virulence. While my recent publication described this phenomenon, the mechanism by which MTA is sensed by S. Typhimurium and suppresses bacterial virulence remains unknown. Further, while we have described that concentrations of MTA change in serum during Salmonella infection, we have not previously explored the possibility that the concentrations of this metabolite change in the gut during a natural model Salmonella infection. If the metabolite is present at different concentrations in the gut during infection, it is unknown whether these changes in concentration have consequences on the bacteria’s ability to successfully colonize the gut. This proposal will address my hypothesis that host MTA can shape disease outcomes by suppressing S. Typhimurium virulence during infection. This would represent a novel example of host- pathogen cross-talk shaping infection outcomes in the gut. The purpose of this grant is to develop a mechanistic understanding of how S. Typhimurium senses and responds to MTA, and to explore the implications of this sensing on host-pathogen cross-talk during infection. To address this, I will measure spatial and temporal MTA regulation along the murine gut and test the ability for host-produced MTA to suppress S. Typhimurium virulence in vivo. I will then pair proteomic, genomic, and transcriptomic approaches to elucidate the molecular mechanisms that enable MTA mediated suppression of S. Typhimurium virulence. Together, these findings will inform the long term goal of this project- which is to to understand how manipulating host and/or bacterial methionine metabolism could be leveraged to improve Salmonella infection outcomes.