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： 沙门氏菌血清鼠伤寒（S. typhimurium）是胃肠炎和非 - 伤寒细菌在全球范围内。我们实验室的先前工作证明了代谢物， 甲基噻吩并腺苷（MTA）能够将宿主对伤寒链霉菌的反应模块。我最近的工作 证明该分子在鼠伤寒沙门氏菌侵袭中起着第二作用，其中MTA直接 通过表达沙门氏菌致病岛1和鞭毛菌抑制伤寒链霉菌病毒 Regulon。反过来，这抑制了细菌侵入肠中细胞的能力 导致体内病毒降低。虽然我最近的出版物描述了这种现象，但 鼠伤寒链球菌感知哪种MTA并抑制细菌病毒仍然未知。进一步 我们已经描述了沙门氏菌感染期间血清中MTA的浓度变化，我们没有 先前探讨了这种代谢物在自然中变化的浓度变化的可能性 模型沙门氏菌感染。如果代谢物在感染过程中以不同的浓度存在于不同的浓度，则 尚不清楚这些浓度的变化是否会对细菌成功的能力产生影响 殖民肠道。该提议将解决我的假设，即主机MTA可以塑造疾病的结果 通过抑制感染过程中伤寒链霉菌病毒。这将代表主机的新颖例子 - 病原体交叉反词构成肠道中的感染结果。 这笔赠款的目的是对孢子链球菌的感觉和 对MTA的反应，并探讨这种敏感性对感染期间宿主 - 病原体串扰的影响。 为了解决这个问题，我将测量沿鼠肠道的空间和临时MTA调节，并测试 宿主产生的MTA以抑制体内鼠伤寒链球菌的毒力。然后，我将对蛋白质组学，基因组和 转录组方法阐明了MTA介导的S.的分子机制 伤寒病毒。这些发现一起将为该项目的长期目标提供信息 - 了解如何利用操纵宿主和/或细菌甲基谢谢以改进 沙门氏菌感染结果。