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.

项目摘要/摘要 胃肠道（GI）的植物被影响的密集和潜水的微生物群填充 人类健康。尽管每个个体的物种水平的微生物群组成是 独特的指纹，其在门水平上的组成更加保守。主要的 门是细菌群和企业，其次是蛋白质。肠道微生物群具有 在很大程度上被认为是对肠道病原体的阻力障碍。但是，输入 引起感染性结肠炎的病原体，肠ho骨大肠杆菌（EHEC）O157：H7和 柠檬酸啮齿动物（广泛用作鼠感染的替代EHEC模型， 鉴于EHEC不感染小鼠），因此利用了提示和营养成员提供的提示和营养 微生物群调节其病毒计划。他们感觉几个代谢产物，包括 糖来源，例如岩谷糖和有机酸，例如琥珀酸酯，以衡量GI 生物地理学和精确调节其病毒计划。 EHEC CRA/KDPE/FUSR 信号级联反应在该调节中起着至关重要的作用。 EHEC与 微生物群的不同成员。我们使用每个代表成员的研究 在主要的门，菌落thetatiiotaomicron（杆菌植物），肠球菌粪肠球菌 （Firmicutes）和共生大肠杆菌（Proteeobacteria）表明EHEC病毒表达 响应这些份额以及它们不同组合的多样性。在这个 赠款提案我们旨在解决不同最小微生物群的影响如何影响输入 感染。这些研究将从还原主义者到整体方法，以深入研究 病原体 - 微生物 - 宿主相互作用的机械方面。值得注意的是这些研究 还将与其他肠道病原体有关，例如沙门氏菌和梭状芽胞杆菌 艰难梭菌等共享这些病原体 - 微生物群的几个相互作用策略 与EHEC。因此，该提案的具体目的是：特定目的1。调查影响 EHEC的CRA/KDPE/FUSR信号级联中的微生物群的不同成员。具体的 目标2。研究不同微生物群组成对EHEC感染的影响 肠to。具体目标3。研究不同微生物群在鼠梭菌中的影响 感染。