Helicobacter pylori CagA toxin polymorphism

幽门螺杆菌CagA毒素多态性

• 批准号: 9014292
• 负责人: D. SCOTT MERRELL
• 金额: $ 22.9万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9014292
• 关键词: Affect; Alleles; Animal Model; Animals; Bacteria; C-terminal; Cell Culture Techniques; Cell Line; Cell physiology; Cells; Cytotoxin; Data; Development; Disease; Dysplasia; Epidemiology; Etiology; Gastritis; Genes; Genetic Polymorphism; Gerbils; Goals; Helicobacter Infections; Helicobacter pylori; Human; In Vitro; Individual; Infection; Inflammation; Inflammatory Response; Link; MAPK14 gene; MAPK8 gene; MDCK cell; Malignant Neoplasms; Mediating; Modeling; Monitor; Oncogenes; Pathogenesis; Pathway interactions; Peptic Ulcer; Persons; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Play; Population; Predisposition; Proteins; Role; STAT3 gene; Signal Pathway; Signal Transduction; Stomach; Stomach Diseases; Testing; Time; Tissues; Toxin; Transfection; Type IV Secretion System Pathway; Tyrosine; Tyrosine Phosphorylation; Variant; Virulence Factors; Work; beta catenin; cohort; design; design and construction; global health; malignant stomach neoplasm; novel; novel therapeutics; pathogen; public health relevance; tissue culture

 DESCRIPTION (provided by applicant): H. pylori chronically infects more than 50% of the world's population and is a significant cause of gastritis, peptic ulcer disease and gastric cancer Within the gastric niche, the bacterium interacts with host cells and elaborates a number of virulence factors that influence disease etiology. Chief among these pathogenic determinants is the cytotoxin-associated gene A product, CagA, a protein that is injected into host cells via a Type IV secretion system. Once inside host cells, CagA is tyrosine phosphorylated by host cell Src/Lyn kinases and subsequently alters host cell physiology via interaction with Src homology region 2, phosphatase 2 (SHP-2) and disruption of multiple signaling pathways. These changes are believed to be central to development of H. pylori-induced disease since epidemiological data indicate that persons infected with CagA-positive strains of H. pylori are significantly more likely to develop severe forms of gastric disease than individuals who harbor CagA-negative isolates. Additionally, the C-terminal portion of CagA is polymorphic specifically in the region that undergoes tyrosine phosphorylation. Epidemiologic evidence and in vitro tissue culture studies indicate that this natural CagA polymorphism may be a crucial determinant for the predisposition of infected individuals to develop gastric cancer. However, all of the cell culture studies that have linked CagA polymorphism to enhanced H. pylori modulation of host cell pathways have either used nonisogenic strains of H. pylori or relied upon transfection models. Interpretation of these study results is complicated by the fact that H. pylori shows a remarkably high degree of strain variation, and transfection studies likely do not accurately mimic bacterial delivery of CagA during the course of a natural infection. Our lab has designed and constructed isogenic strains of H. pylori that differ only in the C-terminal phosphorylation domain of the CagA protein and herein we propose to use these novel strains to aid our long term goal of understanding H. pylori pathogenesis by defining the role of CagA polymorphism in host cell changes and disease development using a short-term gastric cancer small animal model.

 描述（由申请人提供）：H。幽门螺杆菌慢性感染超过50%的世界人口，并且是胃炎、消化性溃疡疾病和胃癌的重要原因。在胃生态位内，细菌与宿主细胞相互作用，并产生影响疾病病因的许多毒力因子。这些致病决定因素中的主要是细胞毒素相关基因A产物CagA，一种通过IV型分泌系统注入宿主细胞的蛋白质。一旦进入宿主细胞，CagA被宿主细胞Src/林恩激酶酪氨酸磷酸化，随后通过与Src同源区2、磷酸酶2（SHP-2）的相互作用和多种信号传导途径的破坏来改变宿主细胞生理学。这些变化被认为是H. pylori引起的疾病，因为流行病学数据表明感染CagA阳性H.幽门螺杆菌感染者比携带CagA阴性分离株的个体更容易患上严重的胃病。此外，CagA的C-末端部分是多态性的，特别是在经历酪氨酸磷酸化的区域。流行病学证据和体外组织培养研究表明，这种天然CagA多态性可能是受感染个体发生胃癌的易感性的关键决定因素。然而，所有将CagA多态性与H.幽门螺杆菌调节宿主细胞途径使用了H. pylori感染或依赖于转染模型。这些研究结果的解释是复杂的事实，H。幽门螺杆菌显示出显著高度的菌株变异，并且转染研究可能不能准确地模拟自然感染过程中CagA的细菌递送。本实验室设计并构建了H. pylori的不同之处仅在于CagA蛋白的C-末端磷酸化结构域，在此，我们建议使用这些新菌株来帮助我们理解H. pylori发病机制，通过使用短期胃癌小动物模型定义CagA多态性在宿主细胞变化和疾病发展中的作用。