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

幽门螺杆菌会感染人的胃粘膜，导致慢性胃炎、溃疡，最终导致胃癌。病原菌利用β1整合素和癌胚抗原相关细胞黏附分子(CEACAM)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。胃上皮形成一层紧密的上皮细胞，由连接复合体(缝隙连接、紧密连接、粘连连接、桥粒、CEACAM等)紧密连接。CEACAM通常位于胃上皮的交界处和顶端，而β1整合素位于基底外侧。在这个项目中，我们想要研究幽门螺杆菌在类活体条件下与这些受体，特别是与β1整合素接触的策略和机制，以便能够将其癌蛋白CagA注入这些细胞。因此，我们寻找新的细菌粘附素和宿主细胞受体，并试图在分子水平上了解幽门螺杆菌粘附素-CEACAM的相互作用，以更好地了解其中涉及的信号事件。此外，我们开发了复杂的新型细胞培养模型，作为紧密的单层生长来研究这些问题。最后，我们计划应用亲和力成熟的CEACAM免疫球蛋白样可变区(IGV)在体外和体内适当的动物模型中干扰CagA的易位。

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.