Sugar regulation of EHEC virulance

EHEC毒力的糖调节

• 批准号: 10599476
• 负责人: ANTHONY W MARESSO
• 金额: $ 61.18万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599476
• 关键词: Address; Affect; Applications Grants; Bacterial Adhesins; Bacteroides; Bacteroidetes; Biological Models; Carbon; Citrobacter rodentium; Clostridium difficile; 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; Infectious colitis; 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.

项目概要/摘要 胃肠道 (GI) 中充满了密集且多样化的微生物群，这些微生物群会影响 人类健康。尽管每个个体在物种水平上的微生物群组成是 作为指纹一样独特，其在门水平上的组成更加保守。占主导地位的 门是拟杆菌门和厚壁菌门，其次是变形菌门。肠道微生物群有 在很大程度上被认为是对肠道病原体的抵抗屏障。然而，肠溶 引起传染性结肠炎的病原体、肠出血性大肠杆菌 (EHEC) O157:H7 和 啮齿类柠檬酸杆菌（广泛用作鼠类感染的肠出血性大肠杆菌替代模型， 鉴于肠出血性大肠杆菌不会感染小鼠），利用成员提供的线索和营养 微生物群来调节其毒力程序。他们感知多种代谢物，包括 糖源（如岩藻糖）和有机酸（如琥珀酸）来测量 GI 生物地理学并精确调控其毒力程序。 EHEC Cra/KdpE/FusR 信号级联在这种调节中起着至关重要的作用。 EHEC 与 EHEC 之间的关系 不同的微生物群成员有所不同。我们的研究使用了每个组织的代表成员 主要门类：Bacteroides thetatiotaomicron（Bacteroidetes）、粪肠球菌 （厚壁菌门）和共生大肠杆菌（变形菌门）表明 EHEC 毒力表达 对这些共生体以及它们的不同组合的反应各不相同。在这个 拨款提案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。这些研究将从还原论到整体方法来深入研究 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，例如肠道沙门氏菌和梭状芽胞杆菌 艰难梭菌等，它们共享一些病原体-微生物群相互作用策略 与肠出血性大肠杆菌。因此，该提案的具体目标是： 具体目标 1. 调查影响 EHEC 的 Cra/KdpE/FusR 信号级联中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 肠类。具体目标 3. 研究不同微生物群对 C. rodentium 鼠的影响 感染。