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

• Applicants: Professor Dr. Markus Gerhard; Professor Dr. Gunther Wennemuth, since 3/2023
• Subject Area: Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 465689316

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.

• DFG Programme: Research Grants
• International Connection: Belgium, China, USA
• Cooperation Partners: Professorin Dr. Pradipta Ghosch; Professorin Kai-feng Pan, Ph.D.; Professor Han Remaut, Ph.D.
• Ehemaliger Antragsteller: Privatdozent Dr. Bernhard B. Singer, until 3/2023 (†)