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

项目总结(项目1) 幽门螺杆菌和伤寒沙门氏菌都是严格适应人类的病原体 它们定植于胃和肠道，是全球范围内的主要公共卫生威胁，对 社会经济资源较低的人口。幽门螺杆菌慢性感染世界人口的50%以上 是消化性溃疡和胃癌的主要危险因素。约77%(812,000例)的胃病新病例 2018年癌症可归因于幽门螺杆菌(GLOBOCAN)。胃癌是导致癌症的第三大原因。 2018年全球报告的死亡人数约为783,000人(世卫组织)。伤寒杆菌感染了2000多万人 每年导致超过500,000人死于伤寒。幽门螺杆菌和沙门氏菌都已经进化 慢性定植于人粘膜表面并逃避宿主天然清除的分子适应 和适应性免疫反应。此外，这两种疾病都变得越来越难以治疗，因为 抗生素耐药性和对其持久性机制缺乏了解。我们将解决这些新出现的问题 利用人源性胃肠有机化合物的新型仿生平台存在的问题包括 1)一种逆转三维上皮类器官分化的方法 用于感染研究的暴露根尖表面的悬浮液，2)诱导肠道分化的方法 微折叠(M)细胞；3)气液界面培养法保存内源性粘膜免疫 系统。我们将使用这些平台来解决难以建模的问题，包括：1)定义和 操纵关键的生态位，使细菌在上皮表面定植，2)阐明特化 粘膜中的侵袭部位和细胞内复制，以及3)了解继发性激活 控制细菌定植和疾病的上皮细胞的免疫反应和免疫反馈 进步。这些研究将导致确定新的途径，可以作为新的目标 非殖民化、治疗学和疫苗战略。

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.