Nuclear function of CagA

Infections with Helicobacter pylori (H. pylori) are closely associated with the induction and progression of inflammation-driven stomach cancer and MALT lymphoma. The risk of developing these diseases is significantly increased by the expression of the H. pylori virulence factor cytotoxin-associated gene A (CagA). CagA is a bacterial oncoprotein that is injected into infected host cells where it acts as a key signaling molecule in carcinogenesis. In contrast to epithelial cells, CagA is cleaved in immune cells into an N-terminal and a C-terminal CagA fragment. However, the functional consequences of CagA fragmentation in immune cells is completely unknown. In this project, we will investigate a novel and sophisticated mechanism of how CagA fragments regulate macrophage functions by combining innovative -omics technologies with classical molecular and cell biology assays to study novel functions of CagA in vitro and in vivo. The transcriptional signature induced by CagA fragments will be identified by RNA-Seq and ATAC-Seq experiments. The molecular mechanism will be investigated by ChIP-Seq, EMSA, luciferase reporter assays, and co-immunoprecipitation assays followed by mass spectrometry. ELISA, flow cytometry and multiplex technologies will be performed to analyze effects on macrophage polarization, phagocytosis, and antigen presentation. In vivo experiments in Mongolian gerbils will provide information on colonization and pathogenesis. The data from this project will contribute to a new understanding of the complex H. pylori pathogenesis and could provide novel approaches for the treatment of H. pylori-mediated chronic inflammation and gastric cancer.