Sugar regulation of EHEC virulence

肠出血性大肠杆菌毒力的糖调节

• 批准号: 10203813
• 负责人: ANTHONY W MARESSO
• 金额: $ 63.88万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10203813
• 关键词: Address; Affect; Applications Grants; Bacterial Adhesins; Bacteroides; Bacteroidetes; Biological Models; Carbon; Citrobacter rodentium; Clostridium difficile; Colitis; Colon; Communities; Complex; Cues; Data; Disease; Disease Outcome; Disease susceptibility; Enteral; Enterococcus faecalis; Enterocytes; Environment; Epithelial; Escherichia coli; Escherichia coli EHEC; Escherichia coli Infections; Escherichia coli O157:H7; Fingerprint; Firmicutes; Fucose; Gastrointestinal tract structure; Gene Expression; Genetic Transcription; Goals; Growth; Harvest; Health; Human; In Vitro; Individual; Infection; Lead; Lesion; Mediating; Metabolic; Metabolism; Mucous body substance; Mus; Nutrient; Pathogenicity Island; Play; Proteobacteria; Regulation; Resistance; Role; Salmonella enterica; Signal Transduction; Source; Succinates; System; Virulence; Virulence Factors; Work; design; enteric infection; enteric pathogen; experimental study; gastrointestinal; gut colonization; gut microbiota; holistic approach; host microbiota; member; microbiota; model building; mouse model; mucinase; organic acid; pathogen; programs; receptor; response; sugar

Project Summary/Abstract The gastrointestinal (GI) tract is populated by a dense and diverse microbiota that impacts human health. Although the microbiota composition at the species level for each individual is unique as a fingerprint, its composition at the phyla level is more conserved. The predominant phyla are Bacteroidetes and Firmicutes, followed by Proteobacteria. The gut microbiota has been largely regarded as a resistance barrier towards enteric pathogens. However, the enteric pathogens that cause infectious colitis, enterohemorrhagic E. coli (EHEC) O157:H7 and Citrobacter rodentium (extensively used as a surrogate EHEC model for murine infections, given that EHEC does not infect mice), exploit cues and nutrients made available by members of the microbiota to regulate their virulence program. They sense several metabolites, including sugar sources such as fucose, and organic acids such as succinate to gauge the GI biogeography and precisely regulate their virulence programs. The EHEC Cra/KdpE/FusR signaling cascade plays a crucial role in this regulation. The relationship between EHEC and different members of the microbiota varies. Our studies using a representative member of each of the main phyla, Bacteroides thetatiotaomicron (Bacteroidetes), Enterococcus faecalis (Firmicutes) and commensal E. coli (Proteobacteria) suggest that EHEC virulence expression varies in response to these commensals, as well as to different combinations of them. In this grant proposal we aim to address how different minimal microbiota compositions impact enteric infections. These studies will build from reductionist to holistic approaches to delve into mechanistic aspects of pathogen-microbiota-host interactions. It is notable that these studies will also be relevant to other enteric pathogens, such as Salmonella enterica and Clostridium difficile, among others, which share several of these pathogen-microbiota interaction strategies with EHEC. Hence the specific aims of this proposal are: Specific Aim 1. Investigate the impact of different members of the microbiota in EHEC’s Cra/KdpE/FusR signaling cascade. Specific Aim 2. Investigate the impact of different microbiota compositions on EHEC infection of enteroids. Specific Aim 3. Investigate the impact of different microbiotas in C. rodentium murine infections.

项目总结/摘要 胃肠道（GI）由密集而多样的微生物群组成， 人体健康尽管每个个体在物种水平上的微生物群组成是 作为一种独特的指纹，它在门一级的组成更为保守。的主要 门是拟杆菌门和厚壁菌门，其次是变形菌门。肠道微生物群 在很大程度上被认为是对肠道病原体的抗性屏障。然而，肠 引起传染性结肠炎的病原体，肠出血性大肠杆菌。大肠杆菌（EHEC）O 157：H7和 啮齿类柠檬酸杆菌（广泛用作鼠感染的替代EHEC模型， 考虑到肠出血性大肠杆菌不会感染小鼠）， 来调节它们的毒力程序它们能感应到几种代谢物， 糖源如岩藻糖和有机酸如琥珀酸盐，以测量GI 精确调控它们的毒力程序。EHEC Cra/KdpE/FusR 信号级联在这种调节中起着至关重要的作用。肠出血性大肠杆菌与 不同的微生物群成员是不同的。我们的研究使用了每一个代表性的成员 主要门，拟杆菌thetatiotaomicron（拟杆菌），粪肠球菌 （Firmicutes）和嗜热菌E.大肠杆菌（变形菌门）表明，EHEC毒力表达 不同的反应，这些广告，以及他们的不同组合。在这 我们的目标是解决不同的最小微生物群组成如何影响肠道 感染.这些研究将建立从还原到整体的方法，深入研究 病原体-微生物群-宿主相互作用的机制方面。值得注意的是，这些研究 也与其他肠道病原体有关，如沙门氏菌和梭菌 difficile等，它们共享这些病原体-微生物群相互作用策略中的一些 关于EHEC因此，本提案的具体目标是：具体目标1。调查的影响 EHEC的Cra/KdpE/FusR信号级联中的不同微生物群成员。具体 目标2.研究不同微生物群组成对肠出血性大肠杆菌感染的影响， 肠状体。具体目标3。研究不同微生物对C.鼠类 感染.