Project 1: Biomimetic Interactions Between Bacterial Pathogens and the Gastrointestinal Epithelium

PROJECT SUMMARY (Project 1) Helicobacter pylori and Salmonella enterica serovar Typhi (Typhi) are both strictly human-adapted pathogens that colonize the stomach and intestine and are major public health threats worldwide that disproportionally affect populations with lower socioeconomic resources. H. pylori chronically infects over 50% of the world population and is the main risk factor for peptic ulcers and gastric cancer. About 77% (812,000) of new cases of gastric cancer were attributable to H. pylori in 2018 (GLOBOCAN). Gastric cancer is the 3rd leading cause of cancer death worldwide with about 783,000 deaths reported in 2018 (WHO). Typhi infects more than 20 million people yearly and causes over 500,000 deaths annually from Typhoid fever. Both H. pylori and Salmonella have evolved molecular adaptations to chronically colonize human mucosal surfaces and evade clearance from host innate and adaptive immune responses. In addition, both are becoming increasingly difficult to treat because of rising antibiotic resistance and poor understanding of their persistence mechanisms. We will address these emerging problems by leveraging novel biomimetic platforms of human-derived gastric and intestinal organoids including 1) a method to reverse the polarity and control the differentiation of three-dimensional epithelial organoids in suspension to expose the apical surface for infection studies, 2) a method to induce differentiation of intestinal microfold (M) cells, and 3) an air-liquid interface culture method to preserve the endogenous mucosal immune system. We will use these platforms to address difficult-to-model problems, including: 1) defining and manipulating critical niches that enable bacterial colonization of the epithelial surface, 2) elucidating specialized sites of invasion and intracellular replication in the mucosa, and 3) understanding secondary activation of immune responses and immune feedback on the epithelium that control bacterial colonization and disease progression. These studies will lead to the identification of new pathways that could serve as novel targets for decolonization, therapeutics, and vaccine strategies.