Structural and functional consequences of the CEACAM-HopQ mediated binding of Helicobacter pylori to human gastric epithelial cells in vitro and in vivo

幽门螺杆菌感染是世界上最常见的慢性细菌感染，影响世界一半的人口。它导致所有受影响的患者的慢性胃炎，在某些情况下甚至导致胃溃疡和胃癌。细菌对胃上皮的粘附对于宿主的定殖和诱导此类疾病至关重要。H.幽门螺杆菌表达能够与宿主细胞特异性相互作用的各种粘附素。对于其中之一，即所谓的HopQ，我们能够证明它可以特异性结合癌胚抗原相关细胞粘附分子家族（CEACAMs）的成员。一般来说，CEACAMs是影响许多功能的细胞-细胞通讯分子，并且已经被描述为其他细菌蛋白的受体。在晶体学研究中，我们已经能够确定确切的HopQ-CEACAM 1相互作用位点。此外，我们发现HopQ结合解决了CEACAM 1的二聚体/寡聚体组织，使得单体CEACAM 1可用于其他相互作用伴侣。有趣的是，我们进一步的研究表明，HopQ-CEACAM的结合是至关重要的CagA易位，一种机制，H。幽门介导的致癌作用初步结果表明，免疫细胞活性受到HopQ-CEACAM 1相互作用的抑制。然而，由HopQ-CEACAM结合诱导的分子机制和信号通路尚不清楚。因此，我们的目标是获得更深入的分子和功能的理解的过程中诱导的H。pylori HopQ。我们将表征CEACAM的调节和信号通路的调节与HopQ的相互作用最初在体外。在CEACAM 1人源化小鼠模型中，我们将使用我们建立的感染模型研究体内结合的后果。特别是，我们将用干扰HopQ-CEACAM相互作用的肽和抗体进行治疗实验。这可能为预防H的发展提供可能的治疗干预选择的基本见解。幽门螺杆菌相关的疾病。

The infection with Helicobacter pylori is the most common chronic bacterial infection worldwide and affects half of the world's population. It leads to chronic gastritis in all affected patients, in some cases even to gastric ulcer and gastric carcinoma. The adhesion of the bacteria to the gastric epithelium is of central importance for the colonization of the host and for the induction of such diseases. H. pylori expresses various adhesins that enable specific interaction with the host cells. For one of them, the so-called HopQ, we were able to show that it can bind specifically to members of the CarcinoEmbryonic Antigen-related Cell Adhesion Molecule Family (CEACAMs). In general, CEACAMs are cell-cell communication molecules that influence numerous functions and have already been described as receptors for other bacterial proteins. In crystallographic studies we have been able to identify the exact HopQ-CEACAM1 interaction sites. Furthermore, we found that HopQ binding resolves the dimere/oligomeric organization of CEACAM1 so that the monomeric CEACAM1 is available for other interaction partners. Interestingly, our further investigations showed that the HopQ-CEACAM binding is of central importance for CagA translocation, a mechanism essential for H. pylori-mediated carcinogenesis. Initial results suggest that immune cell activity is suppressed by the HopQ-CEACAM1 interaction. However, the molecular mechanisms and signalling pathways induced by the HopQ-CEACAM binding are unclear. Therefore, we aim at gaining a deeper molecular and functional understanding of the processes induced by H. pylori HopQ. We will characterize the CEACAM regulation and the signaling pathways regulated by the interaction with HopQ initially in vitro. In a CEACAM1 -humanized mouse model we will then investigate the consequences of binding in vivo using our established infection model. In particular, we will perform therapeutic experiments with peptides and antibodies that interfere with HopQ-CEACAM interaction. This could provide fundamental insights into possible therapeutic intervention options to prevent the development of H. pylori-associated diseases in the future.