Sugar regulation of EHEC virulence

项目摘要/摘要 胃肠道(GI)由密集和多样化的微生物区系组成，这些微生物区系对 人类健康。尽管每个个体在物种水平上的微生物区系组成是 作为指纹的独特之处，其在门水平上的组成更为保守。占优势的 菌门为拟杆菌和菌丝，其次是变形杆菌。肠道微生物区系有 在很大程度上被认为是对肠道病原体的抵抗屏障。然而，肠道 引起传染性结肠炎、肠出血性大肠杆菌O157：H7和 轮状柠檬酸杆菌(广泛用作小鼠感染的代用EHEC模型， 鉴于EHEC不会感染老鼠)，利用成员提供的线索和营养 来调节它们的毒力程序。他们感觉到几种代谢物，包括 糖的来源，如岩藻糖，和有机酸，如琥珀酸，以测量GI 并精确地调节它们的毒力程序。EHEC CRA/KdpE/FusR 信号级联在这一调控中起着至关重要的作用。EHEC与EHEC的关系 微生物区系的不同成员各不相同。我们的研究使用了各自的代表成员 在主要的类群中，塞氏拟杆菌(拟杆菌)，粪肠球菌 和共生大肠杆菌(变形杆菌)提示EHEC毒力表达 对这些共同点以及它们的不同组合的反应是不同的。在这 资助提案我们的目标是解决不同的最小微生物区系组成如何影响肠道 感染。这些研究将从简化论到整体主义方法进行深入研究 病原体-微生物-宿主相互作用的机制方面。值得注意的是，这些研究 也会与其他肠道病原体有关，如肠沙门氏菌和梭状芽孢杆菌 艰难杆菌等，它们分享了几种病原体-微生物区系相互作用的策略 与EHEC合作。因此，这项建议的具体目标是：具体目标1.调查影响 EHEC的CRA/KdpE/FusR信号级联中不同的微生物区系成员。特定的 目的2.研究不同微生物区系组成对肠出血性肠出血性大肠杆菌感染的影响 肠状突。具体目的3.研究不同微生物区系对小鼠轮齿芽孢杆菌的影响 感染。

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.