Activation of alternative NF-kB signaling in the stomach: link to H. pylori virulence factors and effect on gastric inflammation and gastric pathogenesis

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Helicobacter pylori (H. pylori) infection is one of the most prevalent infections worldwide. The chronic gastric inflammation induced by the bacterium might eventually progress to a more severe pathology and finally to gastric cancer. In this process, different host signaling pathways triggered by H. pylori play a decisive role. Of those, the role of canonical NF-kB pathway during H. pylori infection has been extensively studied. Conversely, the involvement of the alternative, so called non-canonical, arm of NF-kB signaling for gastric pathology related to H. pylori remains unclear. We have made preliminary findings indicating involvement of this alternative arm in H. pylori induced inflammatory response. Thus, we propose to perform a comprehensive analysis in vitro as well as in vivo in order to investigate the activation of alternative NF-kB signaling by H. pylori through lymphotoxin b receptor (LTbR) and to elucidate the molecular mechanisms implicated, paying special attention to bacterial virulence factors involved. In addition, by blocking or agonistically activating LTbR in vivo, we aim at deciphering the contribution of alternative NF-kB activation via LTbR-signaling to gastric pathology induced by H. pylori infection. Finally, we plan to specifically express LTs in the stomach to evaluate its involvement in gastric pathogenesis with and without H. pylori infection. Taken together, these experiments will enable us to establish a causal link between LT expression and LTbR-mediated activation of alternative NF-kB to gastric pathogenesis, particularly in the context of H. pylori infection.