Protein phosphorylation and Campylobacter jejuni pathogenesis

蛋白质磷酸化和空肠弯曲菌发病机制

• 批准号: 10448142
• 负责人: STUART A THOMPSON
• 金额: $ 23.1万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-11 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10448142
• 关键词: 5 year old; Acute; Acute Diarrhea; Adherence; Affect; Anabolism; Aspartate; Bacteria; Bacterial Physiology; Biochemical; Biological Assay; Birds; Campylobacter; Campylobacter jejuni; Cattle; Cell Wall; Cells; Cessation of life; Characteristics; Chemoreceptors; Chemotaxis; Child; Complex; Country; Data; Defect; Development; Disease; Domestic Fowls; Environment; Exposure to; Flagella; Food Contamination; Food Processing; Freezing; Gastroenteritis; Gene Expression; Gene Expression Regulation; Genetic; Goals; Guillain Barré Syndrome; High Prevalence; Human; Infection; Ingestion; Interruption; Intervention; Intestines; Invaded; Lead; Maps; Meat; Mediating; Membrane; Metabolism; Microbial Biofilms; Movement; Mucous body substance; Mutation; Mutation Analysis; Nature; Organelles; Paralysed; Pathogenesis; Pathogenicity; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphoserine; Phosphotransferases; Process; Production; Protein Dephosphorylation; Protein Serine/Threonine Phosphatase; Protein phosphatase; Protein-Serine-Threonine Kinases; Proteins; Refrigeration; Reiter Disease; Research; Role; Rotation; Route; Serine; Serine/Threonine Phosphorylation; Signal Transduction; Site-Directed Mutagenesis; Swimming; System; Tertiary Protein Structure; Testing; Threonine; Threonine Phosphorylation Site; Time; Transducers; Virulence; Virulence Factors; Water; Work; bacterial metabolism; base; cell motility; druggable target; extracellular; genetic regulatory protein; host colonization; in vivo; novel; pathogen; pathogenic bacteria; phosphoproteomics; prevent; protein function; response; transmission process; wild bird

ABSTRACT Campylobacter jejuni is a primary bacterial cause of gastroenteritis in the US and throughout the world, with 140 million cases worldwide and 1.3 million cases of C. jejuni gastroenteritis in the US 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, as well as reactive arthritis and other sequelae. Despite the high prevalence of Campylobacter disease and some 40 years of research, the mechanisms by which C. jejuni causes disease remain incompletely understood and severely understudied. Phosphorylation of aspartate residues of bacterial regulatory proteins is a well-known mechanism for mediating changes in gene expression. However, it is increasingly recognized that phosphorylation of proteins at serine/threonine (S/T) residues also modifies protein function. The S/T phosphorylation system uses specific kinases to phosphorylate proteins, and phosphatases to remove the phosphates from S/T residues, in response to environmental signals. Importantly, this occurs in bacterial pathogens, modifying many virulence-associated characteristics. For the first time, our preliminary studies indicate provide new evidence that C. jejuni S/T phosphorylates eight proteins related to the critical pathogenic determinants of motility/chemotaxis, suggesting that S/T phosphorylation modulates C. jejuni virulence. We will define the S/T phosphorylation system in C. jejuni, according to the following hypothesis: Overall Hypothesis: C. jejuni phosphorylates proteins at S/T residues to modulate motility/chemotaxis and related pathogenesis characteristics, by means of novel S/T kinases/phosphatases. We propose a detailed study of protein S/T phosphorylation in C. jejuni, focusing on the mechanism by which the phosphorylation of motility/chemotaxis-related proteins affects their functions, as well as determining the proteins that affect the levels of S/T phosphorylation. We will use a combination of genetic, biochemical, and advanced phosphoproteomics approaches to achieve the goals outlined in these two specific aims: Aim 1. Determine the role of S/T phosphorylation for the function of motility/chemotaxis-related proteins, and Aim 2. Determine the roles of putative S/T kinase/phosphatase proteins in modifying C. jejuni proteins. Together, these will lay the groundwork for our long-term goal of identifying druggable targets to interrupt C. jejuni S/T phosphorylation and interrupting inter-host transmission and pathogenesis in humans.

抽象的 弯曲杆菌的空肠是美国及世界各地的gastroentris的主要双手停止，有140 每年美国，全球有百万个病例和130万例肠炎肠炎 每年约30,000人死亡，主要是在欠发达国家<5岁的儿童。 空肠疾病是零星的，是由于污染的食物（尤其是家禽）和环境暴露而引起的 水域。 世界上急性瘫痪的原因，以及反应性关节炎和其他后遗症。 弯曲杆菌疾病和大约40年的研究，梭状芽胞杆菌引起疾病的机制 保持不完全理解和深入研究。 细菌调节蛋白的天冬氨酸残基的磷酸化是一种众所周知的机制 介导基因表达的变化。 丝氨酸/苏氨酸（S/T）残基也会修饰蛋白质功能。 激酶以磷酸化蛋白质和磷酸化以从S/T残基中去除磷酸盐，呼吸中 至关重要的是，这是在吸收性病原体中的 我们的特征是第一次，我们的预审提供了新的证据 磷酸化八种与运动/趋化性的关键病原体决定因素有关的蛋白质，表明 S/T磷酸化调节了空肠梭状芽孢杆菌。 Jejuni，根据以下假设： 总体假设：空肠梭菌将S/T残基的蛋白质磷酸化至模块化/趋化性和趋化性 相关的发病机理特征，通过新型的S/T激酶/磷酸酶。 我们提出了一项详细研究的蛋白质S/t磷酸化链球菌的磷酸化，重点是该机制 运动/趋化性相关蛋白的磷酸化会影响其功能，并确定它们 影响S/T水平的蛋白质 先进的磷蛋白组学以实现这两个具体目标中概述的目标：目标1。 确定S/T磷酸化对运动/趋化性相关蛋白功能的功能，并AIM 2。 确定推定的S/T激酶/磷酸酶蛋白在修饰Jejuni蛋白中的作用 将为我们的长期目标奠定基础 人类中的磷酸化和中断宿主的传播和发病机理。