Virtually all Helicobacter pylori infected individuals develop inflammation of the gastric mucosa. A complex interplay of bacterial and host genetic factors has been suggested to explain why only a small percentage of infected individuals develop severe diseases including peptic ulcers, gastric adenocarcinoma and gastric MALT lymphoma. In animal studies, increased gastric inflammation is associated with a lower bacterial burden and neutrophils have been shown to play a key role in bacterial clearance. Despite robust recruitment of immune cells during natural infection, without treatment, H. pylori achieves lifelong colonization. H. pylori is known to evade and manipulate host immune defense strategies (e.g. limits Toll-like receptor signaling, induces regulatory T cells to promote chronic persistence) interfering with inflammatory processes presumably to enhance bacterial survival. H. pylori also seems to benefit from limited and localized inflammation. Importantly, development of gastric ulcers and epithelial cell transformation, which leads to cancer, depend on H. pylori?s ability to induce a state of chronic inflammation characterized by neutrophil and lymphocyte infiltration and proinflammatory cytokine production. Inflammatory host responses are initiated by intracellular delivery of CagA toxin via a type 4 secretion system (cag-T4SS). Along with CagA, the cag-T4SS delivers bacterial cell wall fragments into the cytosol of gastric epithelial cells. These fragments are thought to stimulate pathogen recognition receptor NOD1, leading to production of proinflammatory cytokines such as IL-8, a key neutrophil chemoattractant. In gastric epithelial cells, the major driver of the NF-?B-dependent immune response was previously thought to be NOD1. We recently determined that a precursor in H. pylori?s lipopolysaccharide biosynthesis pathway, heptose-1,7- bisphosphate (HBP), is delivered to the host cell via the cag-T4SS where it triggers TRAF-interacting protein with forkhead-associated domain (TIFA)-dependent host signaling leading to a robust NF-?B mediated inflammatory response that precedes NOD1 activation. Our preliminary data also suggests that H. pylori initiates a type 1 interferon (IFN) response in myeloid-derived cells. We hypothesize that H. pylori triggers different host pathogen recognition receptors in gastric epithelial and myeloid-derived cells by delivering bacterial factors through its cag-T4SS, orchestrating the early immune response, which ultimately favors bacterial persistence rather than clearance.
Aim 1 will defined the diversity of innate immune responses to H. pylori infection in gastric epithelial and myeloid-derived cells.
Aim 2 will defined the roles of Nod1 and Tifa-dependent immune responses to H. pylori infection in both epithelial myeloid compartments. TIFA?s role in H. pylori detection has only recently began to be appreciated and the bacterial ligand that triggers the type I IFN response in an H. pylori infected host has not been elucidated. A comprehensive picture of how H. pylori initiates an immune response in gastric epithelial cells versus myeloid-derived cells is ultimately required to understand how the host-pathogen interaction can be manipulated in the host?s favor.
Virtually all Helicobacter pylori infected individuals develop inflammation of the gastric mucosa initiated by host innate immune receptors including NOD1. Our goal is to acquire a comprehensive picture of the early NOD1-dependent and independent events in gastric epithelial cells in response to H. pylori, which is ultimately required to understand how the host-pathogen interaction can be manipulated in the host?s favor. A thorough understanding of NOD1-dependent and independent immune responses will inform strategies for how to achieve just the right amount of inflammation to promote H. pylori clearance, but prevent ulcer and cancer development.
