Host pathogen signaling in the intestine

肠道中的宿主病原体信号传导

• 批准号: 8495261
• 负责人: VANESSA SPERANDIO
• 金额: $ 18.56万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-22 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8495261
• 关键词: Adrenergic Receptor; Animals; Aspartate; Attenuated; Bacteria; Chemicals; Citrobacter rodentium; Enterobacteriaceae; Epinephrine; Escherichia coli EHEC; Escherichia coli O157; G-Protein-Coupled Receptors; Gastrointestinal tract structure; Genes; Genetic Transcription; Grant; Histidine; Homologous Gene; Hormones; Human; Immune; In Vitro; Infant; Infection; Intestines; Mammals; Metabolic; Modeling; Mus; Norepinephrine; OmpR protein; Organism; Oryctolagus cuniculus; Pathogenesis; Phosphorylation; Physiology; Plants; Reporting; Research Personnel; Signal Transduction; Site; Stress; System; Virulence; biological adaptation to stress; gastrointestinal; in vivo; inorganic phosphate; mutant; pathogen; response; sensor histidine kinase; trait; transcription factor

DESCRIPTION (provided by applicant): The deadly gastrointestinal pathogen enterohemorrhagic E. coli (EHEC) O157:H7 exploits sensing the host's stress hormones epinephrine (epi) and norepinephrine (NE) to activate its virulence traits. Stress responses have a profound effect in an organism's physiology and survival, and are also sensed by bacteria as a means to gauge the metabolic and immune state of the host. These hormones in mammals are sensed by adrenergic receptors that are G-coupled protein receptors (GPCRs). Bacteria, however, sense these hormones through histidine sensor kinases (HKs), which act in concert with a response regulator (RR) protein constituting a two-component system. Upon sensing its signal, the HK autophosphorylates in a histidine residue, and then transfers this phosphate to an aspartate residue in its cognate RR. The majority of the RRs are transcription factors, which are activated upon phosphorylation. We have first reported EHEC's two adrenergic receptors: the HKs QseC and QseE with QseE being downstream of QseC in this signaling cascade (given that transcription of qseE is activated through QseC). QseC homologues are present in at least 25 important human and plant pathogens, while the distribution of QseE is limited to enteric bacteria. EHEC qseC and qseE mutants have been shown to be attenuated for virulence in vitro and in vivo using an infant rabbit model of infection However, the study of the true interplay between EHEC and the host through this signaling system has been challenging due to the lack of murine models to study EHEC pathogenesis in the GI tract. Hence, many investigators utilize the natural mouse pathogen Citrobacter rodentium as a surrogate model for EHEC GI pathogenesis in mice. All of the known virulence genes of EHEC have been validated in vivo using C. rodentium murine infections. The utilization of the C. rodentium model capitalizes in merging the powerful genetically tractability of host and pathogen to unravel the mechanisms involved in host recognition and infection. We have shown that epi and NE activate expression of all virulence genes in C. rodentium, in a similar scenario to what we have observed with EHEC (Preliminary results). C. rodentium qseC and qseE mutants are also attenuated for virulence in vitro and in vivo (murine infection) (Preliminary studies), making this a genetically tractable model to dissect the contribution of host chemical signals during pathogenesis. In accordance, the Specific Aim of this application is: Characterize the contribution of the host Epi/NE hormones to C. rodentium pathogenesis during murine infection.

描述（由申请人提供）：致命的胃肠道病原体肠出血性大肠杆菌 (EHEC) O157:H7 利用感知宿主的应激激素肾上腺素 (epi) 和去甲肾上腺素 (NE) 来激活其毒力特征。 应激反应对生物体的生理和生存具有深远的影响，并且也被细菌感知，作为衡量宿主代谢和免疫状态的一种手段。哺乳动物体内的这些激素由肾上腺素能受体 G 偶联蛋白受体 (GPCR) 感知。然而，细菌通过组氨酸传感器激酶 (HK) 感知这些激素，组氨酸传感器激酶 (HK) 与构成双组分系统的反应调节器 (RR) 蛋白协同作用。在感应到其信号后，HK 在组氨酸残基中自磷酸化，然后将该磷酸盐转移到其同源 RR 中的天冬氨酸残基。大多数 RR 是转录因子，在磷酸化后被激活。我们首先报道了EHEC的两种肾上腺素能受体：HKs QseC和QseE，其中QseE在此信号级联中位于QseC的下游（假设qseE的转录是通过QseC激活的）。 QseC 同源物存在于至少 25 种重要的人类和植物病原体中，而 QseE 的分布仅限于肠道细菌。使用婴儿兔感染模型，EHEC qseC 和 qseE 突变体已被证明在体外和体内毒力减弱。然而，由于缺乏 EHEC 和宿主通过该信号系统之间的真正相互作用的研究一直具有挑战性。研究胃肠道肠出血性大肠杆菌发病机制的小鼠模型。因此，许多研究人员利用天然小鼠病原体啮齿类柠檬酸杆菌作为小鼠肠出血性大肠杆菌（EHEC）胃肠道发病机制的替代模型。所有已知的肠出血性大肠杆菌的毒力基因均已通过啮齿类梭菌感染在体内得到验证。利用啮齿类动物模型，将宿主和病原体强大的遗传易处理性结合起来，以揭示宿主识别和感染的机制。我们已经证明，epi 和 NE 会激活啮齿类弯曲杆菌中所有毒力基因的表达，这与我们在肠出血性大肠杆菌中观察到的情况类似（初步结果）。 C. rodentium qseC 和 qseE 突变体在体外和体内（小鼠感染）的毒力也减弱（初步研究），使其成为一个遗传易处理的模型，可用于剖析宿主化学信号在发病过程中的贡献。因此，本申请的具体目标是：表征小鼠感染期间宿主 Epi/NE 激素对啮齿类弯曲杆菌发病机制的贡献。