Mechanisms of methylthioadenosine signaling during Salmonella infection

沙门氏菌感染期间甲硫腺苷信号传导机制

• 批准号: 9980693
• 负责人: Jeffrey Bourgeois
• 金额: $ 3.77万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980693
• 关键词: Address; Antibiotics; Bacteremia; Bacteria; Binding; Bioavailable; Catabolism; Cells; Cues; DNA Methylation; Data; Diagnostic; Disease Outcome; Flagella; Gastroenteritis; Gastrointestinal tract structure; Gene Expression; Genes; Genomics; Germ-Free; Goals; Grant; Immune response; Impairment; Infection; Inflammation; Intestines; Invaded; Knock-out; Longevity; Lysine; Mass Spectrum Analysis; Measures; Mediating; Metabolic; Methionine; Methionine Metabolism Pathway; Methylation; Modeling; Molecular; Morbidity - disease rate; Multi-Drug Resistance; Mus; Outcome; Pathogenicity Island; Phenotype; Plasma; Play; Post-Translational Protein Processing; Production; Protein Methylation; Proteomics; Publications; Reaction; Regulation; Regulon; Role; Salmonella; Salmonella infections; Salmonella typhimurium; Serum; Shapes; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Testing; Therapeutic; Vaccines; Variant; Virulence; Virulence Factors; Work; base; design; fitness; gut colonization; improved; in vivo; inhibitor/antagonist; microbiota; mortality; novel; overexpression; pathogen; pathogenic bacteria; plasma lead; pleiotropism; reconstitution; response; small molecule inhibitor; spatial temporal variation; transcriptome sequencing; transcriptomics

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.

项目摘要/摘要： 肠沙门氏菌鼠伤寒血清型（S. Typhimurium）是胃肠炎和非胃肠炎的主要原因。 我们实验室之前的研究表明，该代谢物， 甲硫腺苷 (MTA) 能够调节宿主对鼠伤寒沙门氏菌的反应。 证明该分子在鼠伤寒沙门氏菌入侵期间发挥第二作用，其中 MTA 直接 通过抑制沙门氏菌致病性 Island-1 和鞭毛来抑制鼠伤寒沙门氏菌毒力 这反过来又抑制细菌侵入肠道细胞、诱发炎症和的能力。 虽然我最近的出版物描述了这种现象，但其机制是通过 哪种 MTA 能被鼠伤寒沙门氏菌感知​​并抑制细菌毒力仍然未知。 我们已经描述了沙门氏菌感染期间血清中 MTA 浓度的变化，但我们还没有 先前探索了这种代谢物的浓度在自然过程中在肠道中发生变化的可能性 如果感染期间肠道中存在不同浓度的代谢物，则模型沙门氏菌感染。 尚不清楚这些浓度的变化是否会对细菌成功地发挥作用的能力产生影响。 该提案将解决我的假设，即宿主 MTA 可以影响疾病结果。 通过在感染过程中抑制鼠伤寒沙门氏菌毒力，这将代表宿主的一个新例子。 病原体串扰影响肠道内的感染结果。 这笔赠款的目的是从机制上理解鼠伤寒沙门氏菌如何感知和 对 MTA 做出反应，并探讨这种传感对感染期间宿主-病原体串扰的影响。 为了解决这个问题，我将测量小鼠肠道的空间和时间 MTA 调节，并测试 然后，我将使用宿主产生的 MTA 来抑制鼠伤寒沙门氏菌体内的毒力。 转录组学方法阐明 MTA 介导的金黄色葡萄球菌抑制的分子机制。 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。