Project 1: Modeling bacterial enteric infections in human organoid culture

项目总结 我们将使用两种人类适应的微生物，它们在全球范围内造成巨大的发病率和死亡率，以探索 有机体技术研究人类特有的胃肠道细菌病原体的潜力。幽门螺杆菌 幽门螺杆菌(Hp)慢性感染超过50%的世界人口的胃，是最重要的风险 与胃癌发生有关的因素。每年有超过70万人死于胃癌。沙门氏菌 伤寒沙门氏菌每年感染2000多万人，造成22万人死亡 每年一次。这两种病原体都可以在人类宿主中持续很长时间，动物也不是 两者都以复杂的方式操纵上皮和免疫系统。每个人都被改编成 到胃肠道的不同区域，因此将作为感染的重要检测病例。 不同类型的人体器官(胃、小肠和结肠)。还有一些未获答复的问题 在动物模型中不能正确解决的问题。例如，尚不清楚 将幽门螺杆菌毒力因子CagA注入胃细胞可促进胃癌。在体外，幽门螺杆菌和CagA 加速上皮细胞增殖，破坏细胞间连接，改变细胞极性，防止细胞凋亡， 并引发炎症反应。我们将使用人体胃类器官来确定幽门螺杆菌是否注射 人胃腺中的caga及其如何影响人上皮中增殖的前体细胞。另一个 该领域悬而未决的问题是伤寒沙门氏菌如何入侵肠道而不引起急性 胃肠炎？为了开始解决这些问题，我们建议1)使用胃器官来模拟 幽门螺杆菌与人胃上皮细胞的相互作用及其对前体细胞和干细胞的影响 2)询问伤寒沙门氏菌如何控制肠道内的免疫反应，以操纵炎症信号并避免 导致急性胃肠炎。

PROJECT SUMMARY We will use two human-adapted microbes that cause tremendous morbidity and mortality worldwide to explore the potential of organoid technology to study human-specific gastrointestinal bacterial pathogens. Helicobacter pylori (Hp) chronically infects the stomachs of over 50% of the world population and is the most important risk factor for the development of gastric cancer. Over 700,000 people die annually from gastric cancer. Salmonella enterica serovar Typhi (S. Typhi) infects more than 20 million people yearly and causes 220,000 deaths annually. Both pathogens can persist over long periods of time in the human host, neither have an animal reservoir, and both manipulate the epithelium and the immune system in sophisticated ways. Each is adapted to a different region of the gastrointestinal tract, and thus will serve as important test cases for infection of different types of human organoids (gastric, small intestine, and colon). There are a number of unanswered questions that cannot be properly addressed in animal models. For example, it is unknown whether the injection of the Hp virulence factor CagA into gastric cells promotes gastric cancer. In vitro, Hp and CagA accelerate epithelial cell proliferation, disrupt the intercellular junctions, alter cell polarity, prevent apoptosis, and induce inflammatory responses. We will use human gastric organoids to determine whether Hp injects CagA in the human gastric glands and how it affects proliferating precursor cells in human epithelium. Another unanswered question in the field is how does Salmonella Typhi invade the intestine without causing acute gastroenteritis? To begin addressing these questions we propose to 1) use gastric organoids to model the interaction between Hp and the human gastric epithelium and focus on its effects on precursor/stem cells and 2) ask how does S.Typhi control immune responses in the gut to manipulate inflammatory signaling and avoid causing acute gastroenteritis.