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

• 批准号: 10196969
• 负责人: STUART A THOMPSON
• 金额: $ 19.25万
• 依托单位: AUGUSTA UNIVERSITY
• 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 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10196969
• 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

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.

摘要 空肠弯曲杆菌是美国和整个美国胃肠炎的主要细菌原因。 世界范围内，全球有1.4亿例病例，130万例C.空肠肠胃炎在美国每年。 这种感染每年导致30 000多人死亡，主要是不发达国家5岁以下的儿童。 大多数C.空肠疾病是散发性，由受污染的食物（特别是家禽）引起， 暴露于环境沃茨。一些C。空肠感染（约1/1，000）导致格林-巴利综合征的发生， Barré综合征，世界上急性瘫痪的主要原因。尽管高流行率， 弯曲杆菌病和近40年的研究，通过C。空肠致病 仍然不完全了解和严重不足的研究。 许多细菌，包括人类病原体，使用第二信使环二GMP（c-di-GMP）， 调节代谢和毒性相关特征。通常，c-di-GMP通过二鸟苷酸合成， 含有GGDEF结构域的环化酶（DGC），并被具有EAL或HD-的磷酸二酯酶（PDE）降解。 GYP域。累积的c-di-GMP与介导下游调节的多种受体结合。 c-di-GMP的影响。细菌c-di-GMP信号网络可能非常复杂;一些细菌有数十个 DGC和PDE被认为整合了许多上游信号并调节蛋白质表达， 相应的活动。与此相反，预测的C.空肠c-di-GMP网络由单个DGC组成，胆汁- 电阻响应调节器CbrR。这是首次对C.空肠。 总体假设：C。空肠使用c-di-GMP信号传导来调节胆汁阻力，运动性/趋化性， 和生物膜的形成。 我们提出了一个详细的研究c-di-GMP介导的基因调控在C。空肠，重点是 二鸟苷酸环化酶CbrR控制胆汁抗性表达的机制， 运动性/趋化性和生物膜形成。我们将结合基因、生化和RNA测序技术， 实现这两个具体目标中概述的目标的方法：目标1）定义CbrR产生的作用 c-di-GMP在C.空肠胆汁阻力、运动性/趋化性和生物膜形成;以及目的2）确定 受CbrR调控的基因。总之，这些将为我们的长期目标奠定基础， 这一新的信号网络和中断宿主间的传播和发病机制在人类。

项目成果

The Campylobacter jejuni Response Regulator and Cyclic-Di-GMP Binding CbrR Is a Novel Regulator of Flagellar Motility.

• DOI: 10.3390/microorganisms10010086
• 发表时间: 2021-12-31
• 期刊: Microorganisms
• 影响因子: 4.5
• 作者: Cox CA;Bogacz M;El Abbar FM;Browning DD;Hsueh BY;Waters CM;Lee VT;Thompson SA
• 通讯作者: Thompson SA

Binding of Campylobacter jejuni FliW Adjacent to the CsrA RNA-Binding Pockets Modulates CsrA Regulatory Activity.

• DOI: 10.3389/fmicb.2020.531596
• 发表时间: 2020
• 期刊: Frontiers in microbiology
• 影响因子: 5.2
• 作者: Bogacz M;El Abbar FM;Cox CA;Li J;Fiedler JS;Tran LKH;Tran PMH;Daugherty CL;Blake KH;Wang Z;Azadi P;Thompson SA
• 通讯作者: Thompson SA