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

项目概要（项目1） 幽门螺杆菌和伤寒沙门氏菌都是严格的人类适应性病原体 它们在胃和肠中定植，是全球范围内的主要公共卫生威胁， 社会经济资源较低的人口。H.幽门螺杆菌慢性感染超过50%的世界人口 是消化性溃疡和胃癌的主要危险因素。约77%（812，000）的新发胃溃疡病例 癌症是由H. pylori in 2018（GLOBOCAN）.胃癌是第三大癌症病因 2018年全球报告了约783，000例死亡（世卫组织）。伤寒感染超过2000万人 每年有超过500，000人死于伤寒。两个都是H.幽门螺杆菌和沙门氏菌 分子适应，以长期定殖于人类粘膜表面，并逃避宿主先天性 和适应性免疫反应。此外，由于全球变暖， 抗生素耐药性和对其持久性机制的了解不足。我们将解决这些新出现的 通过利用人源性胃和肠类器官的新型仿生平台， 1)一种逆转三维上皮类器官的极性并控制其分化的方法， 悬浮液以暴露顶端表面用于感染研究，2）诱导肠上皮细胞分化的方法， 微折叠（M）细胞，和3）气-液界面培养方法，以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 操纵关键的壁龛，使细菌定植的上皮表面，2）阐明专门的 在粘膜中的侵入和细胞内复制的位点，和3）理解 控制细菌定植和疾病的上皮上的免疫应答和免疫反馈 进展这些研究将导致识别新的途径，可以作为新的目标， 去殖民化、治疗和疫苗策略。

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.