Mechanisms of methylthioadenosine signaling during Salmonella infection

项目概要/摘要： 鼠伤寒沙门氏菌（S.鼠伤寒）是胃肠炎的主要原因， 伤寒菌血症在世界范围内。我们实验室以前的工作已经证明了代谢物， 甲基硫代腺苷（MTA）能够调节宿主对S.鼠伤寒我最近的工作 证明了该分子在S.其中MTA直接侵入鼠伤寒 抑制S.通过抑制沙门氏菌致病性岛-1和鞭毛的鼠伤寒毒力 调节子这反过来又抑制了细菌侵入肠道细胞，诱导炎症， 导致体内毒力降低。虽然我最近的出版物描述了这一现象， 其中MTA由S感测。鼠伤寒沙门氏菌和抑制细菌毒力仍然未知。此外，虽然 我们已经描述了沙门氏菌感染期间血清中MTA浓度的变化，但我们没有 先前探索了这种代谢物的浓度在肠道中变化的可能性， 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浓度存在， 目前尚不清楚这些浓度的变化是否会对细菌的成功繁殖能力产生影响。 在肠道中定居这项提议将解决我的假设，即宿主MTA可以影响疾病的结果 通过抑制S.感染过程中的鼠伤寒毒力。这将是一个新的例子，主机- 病原体相互作用影响肠道感染的结果。 这项补助金的目的是发展一个机械的理解如何S。鼠伤寒杆菌感觉和 响应MTA，并探讨感染过程中这种传感对宿主-病原体串扰的影响。 为了解决这个问题，我将测量小鼠肠道沿着MTA的空间和时间调节， 宿主产生的MTA抑制S.体内鼠伤寒毒力。然后，我将对蛋白质组学，基因组学， 转录组学方法来阐明MTA介导的S. 鼠伤寒毒力。总之，这些发现将为该项目的长期目标提供信息，即 了解如何操纵宿主和/或细菌甲硫氨酸代谢可以被利用来改善 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.