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Identification of novel Helicobacter pylori adhesins and host cell receptors facilitating bacterial access to beta1 integrin and translocation of CagA

新型幽门螺杆菌粘附素和宿主细胞受体的鉴定促进细菌接触β1整合素和CagA易位

基本信息

批准号：
195217982
负责人：
Professor Dr. Rainer Haas
金额：
--
依托单位：
Max-von-Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2011
资助国家：
德国
起止时间：
2010-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/195217982?language=en
关键词：
Identification novel Helicobacter pylori adhesins

项目摘要

The bacterial pathogen Helicobacter pylori infects the human stomach mucosa, causing chronic gastritis, ulceration and eventually gastric cancer. Pathogenic strains inject the bacterial oncoprotein Cytotoxin-associated antigen A (CagA) into host cells by exploiting beta1 Integrin and carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) as host cell receptors. The gastric epithelium forms a tight layer of epithelial cells strictly connected by junctional complexes (gap junctions, tight junctions, adherence junctions, desmosomes, CEACAMs, etc.). Whereas CEACAMs are usually located at the junctions and on the apical side of the gastric epithelium, beta1 integrins are located at the basolateral side. In this project we want to study the strategies and mechanisms used by H. pylori to make contact to these receptors, especially to the beta1 integrins, under in vivo-like conditions, in order to be able to inject its oncoprotein CagA into these cells. We therefore search for novel bacterial adhesins and host cell receptors and we try to understand the H. pylori adhesin-CEACAM interaction at the molecular level to better understand the signaling events involved. Furthermore, we developed sophisticated novel cell culture models growing as tight monolayers to study these questions. Finally we plan to apply affinity-maturated CEACAM Immunglobulin-like variable (IgV) domains to interfere with CagA translocation in vitro and in vivo in appropriate animal models.

幽门螺杆菌感染人体胃粘膜，引起慢性胃炎、溃疡并最终导致胃癌。致病性菌株通过利用β 1整合素和癌胚抗原相关细胞粘附分子（CEACAMs）作为宿主细胞受体将细菌癌蛋白细胞毒素相关抗原A（CagA）注入宿主细胞。胃上皮形成由连接复合体（间隙连接、紧密连接、粘附连接、桥粒、CEACAMs等）严格连接的上皮细胞的紧密层。而CEACAMs通常位于交界处和胃上皮的顶侧，β 1整联蛋白位于基底外侧。在本项目中，我们想研究的策略和机制，H。pylori感染，以在体内样条件下与这些受体，特别是β 1整联蛋白接触，以便能够将其癌蛋白CagA注射到这些细胞中。因此，我们寻找新的细菌粘附素和宿主细胞受体，并试图了解H。pylori粘附素-CEACAM相互作用在分子水平上，以更好地了解所涉及的信号事件。此外，我们开发了复杂的新的细胞培养模型生长为紧密的单层来研究这些问题。最后，我们计划在适当的动物模型中应用亲和力成熟的CEACAM免疫球蛋白样可变（IgV）结构域在体外和体内干扰CagA易位。