Campylobacter jejuni cyclic-di-GMP signaling and pathogenesis

空肠弯曲杆菌环二 GMP 信号传导和发病机制

基本信息

批准号：
10043488
负责人：
STUART A THOMPSON
金额：
$ 21.75万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
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/10043488
关键词：
5 year old Acute Acute Diarrhea Anti-Bacterial Agents Antigens Bacteria Bacterial Model Bile fluid Binding Biochemical Birds C-terminal Campylobacter Campylobacter jejuni Caulobacter crescentus Cells Cessation of life Characteristics Chemotactic Factors Chemotaxis Child Complex Country DNA Data Development Dimerization Disease Domestic Fowls Escherichia coli Exposure to Family Food Contamination Gastroenteritis Gastrointestinal tract structure Gene Expression Regulation Gene Proteins Genes Genetic Genetic Transcription Goals Guanosine Triphosphate Guillain-Barré Syndrome High Prevalence Human Infection Interruption Intervention Lead Life Style Link Mediating Metabolic Metabolism Microbial Biofilms N-terminal Orphan Paralysed Pathogenesis Pathogenicity Periodicity Phenotype Phosphorylation Phosphorylation Site Phosphotransferases Play Polysaccharides Production Proteins Proteomics Public Health Publishing Research Resistance Role Second Messenger Systems Serine Signal Pathway Signal Transduction Site Tertiary Protein Structure Testing United States Variant Virulence Virulence Factors Water Work cell motility diarrheal disease diguanylate cyclase efflux pump extracellular genetic regulatory protein host colonization human pathogen mutant novel pathogen phosphoric diester hydrolase prevent protein expression receptor response trait transcriptome sequencing transmission process

项目摘要

ABSTRACT Campylobacter jejuni is a primary bacterial cause of gastroenteritis in the United States and throughout the world, with 140 million cases worldwide and 1.3 million cases of C. jejuni gastroenteritis in the U.S. each year. This infection leads to >30,000 deaths annually, primarily in children <5 years old in underdeveloped countries. Most cases of C. jejuni disease are sporadic and result from contaminated food (especially poultry) and exposure to environmental waters. Some C. jejuni infections (~1/1,000) lead to the development of Guillain- Barré Syndrome, the leading cause of acute paralysis in the world. Despite the high prevalence of Campylobacter disease and nearly 40 years of research, the mechanisms by which C. jejuni causes disease remain incompletely understood and severely understudied. Numerous bacteria, including human pathogens, use the second messenger cyclic-di-GMP (c-di-GMP) to regulate metabolic and virulence-related characteristics. Typically, c-di-GMP is synthesized by diguanylate cyclases (DGCs) containing GGDEF domains, and degraded by phosphodiesterases (PDEs) with EAL or HD- GYP domains. Accumulated c-di-GMP binds to diverse receptors that mediate the downstream regulatory effects of c-di-GMP. Bacterial c-di-GMP signaling networks can be quite complex; some bacteria have dozens of DGCs and PDEs that are thought to integrate numerous upstream signals and adjust protein expression or activity accordingly. In contrast, the predicted C. jejuni c-di-GMP network consists of a single DGC, the bile- resistance response regulator CbrR. This is the first study of c-di-GMP signaling in C. jejuni. Overall Hypothesis: C. jejuni uses c-di-GMP signaling to modulate bile resistance, motility/chemotaxis, and biofilm formation, by means of the divergent diguanylate cyclase response regulator CbrR. We propose a detailed study of c-di-GMP-mediated gene regulation in C. jejuni, focusing on the mechanism by which the diguanylate cyclase CbrR controls the expression of bile resistance, motility/chemotaxis, and biofilm formation. We will use a combination of genetic, biochemical, and RNA-Seq approaches to achieve the goals outlined in these two specific aims: Aim 1) Define the role of CbrR-produced c-di-GMP in C. jejuni bile resistance, motility/chemotaxis, and biofilm formation; and Aim 2) Determine the genes that are regulated by CbrR. Together, these will lay the groundwork for our long-term goal of interrupting this novel signaling network and interrupting inter-host transmission and pathogenesis in humans.

抽象的空肠弯曲杆菌是美国胃肠道的主要双脚，thoushout thee 世界各地有1.4亿例病例，每年在美国有130万病例的空肠肠胃炎病例。这种感染每年导致30,000人死亡，主要是在欠发达国家<5岁的儿童中。大多数空肠梭菌疾病的病例都是零星的，是由受污染的食物（尤其是家禽）和暴露于环境水域。巴雷综合症，世界上急性瘫痪的主要原因。弯曲杆菌疾病和将近40年的研究，旋转梭菌引起疾病的机制保持不完全理解和深入研究。多种细菌（包含人类病原体）使用第二质体环-DI-GMP（C-DI-GMP）调节代谢和病毒相关的特征。含有GGDEF结构域的循环酶（DGC），并由EAL或HD-磷酸二酯酶（PDES）降解 GYP结构域。 C-DI-GMP的影响。 DGC和PDE的被认为会整合大量上游上游信号并调整蛋白质表达或相反的活动。电阻调节剂CBR。总体假设：空肠C.使用C-DI-GMP信号传导调节胆汁耐药性，运动/趋化性，和生物膜形成，通过发散的二甘氨酸酸环化酶反应响应调节剂CBRR。我们提出了一项详细的研究，对J. jejuni中的C-DI-GMP介导的基因调节，重点是二烷基酸环化酶CBR控制胆汁耐药性表达的机制，运动/趋化性和生物膜形成。实现这两个特定目的中概述的目标的方法：目标1）定义CBR生产的作用 C. Jejuni胆汁抗性，运动/趋化性和生物膜的形成和AIM 2）确定由CBRR定期的基因。这个新颖的信号网络并打断了人类的宿主间传播和发病机理。