Our research focuses on the pathogenesis of Helicobacter pyloriby studying both bacterial virulence factors and the relation between H. pylori and its infected host. H. pylori colonizes the stomach of about half the world’s human population. Infection byH. pylori is chronic and can evolve from gastritis to severe pathologies such as peptic ulcers and gastric cancer accounting for about 700 000 deaths per year worldwide. H. pylori is till now the only bacterium to be recognized as a type 1 carcinogenic agent. In addition to this public health issue, H. pylori is of particular interest because it is the only microorganism to persistently colonize the human gastric mucosa, its unique niche, which makes it an excellent model organism to address fundamental questions related to its adaptation to such a hostile acidic environment. We focus on the identification and characterization of H. pylori factors and mechanisms that make this bacterium a successful and persistent pathogen in its unique niche, the acidic stomach. Nickel is an essential element for H. pylori as it is the co-factor of the major virulence and acid-resistance factor, urease that produces large amounts of ammonia. We are characterizing original mechanisms for nickel uptake (TonB-dependent transporter), trafficking (protein complexes and chaperones) and regulation of its homeostasis by a multifaceted transcriptional regulator, NikR. In addition, the cellular management of the massive ammonia production through protein complexes including the virulence factor urease is explored by Tandem Affinity Purification (TAP) and the potential cytotoxicity of their activities is being evaluated with cellular and animal models. Furthermore, we analyze the host response and genotoxicity associated with the infection by H. pylori, in relation with the development of gastric cancer. The role of genetic instabilities and epigenetic alterations associated with H. pylori infection are investigated as well as the related mechanisms and their consequences for the host. Such events play a key role in the early steps of carcinogenesis. We also search for host gene as potential risk factors for the induction of gastric malignancies by H. pylori infection focusing on pleiotropic regulators as transcription factors that could serve as preventive/diagnostic markers associated to gastric cancer.