The in vivo response of the intestinal epithelium to bacterial infection

沙门氏菌能够侵入非吞噬性肠上皮细胞，然后进行细胞内增殖和跨上皮迁移。人类沙门氏菌分离株中负责的分子效应分子的保守性表明了这一步骤在感染发病机制中的关键贡献。虽然在体外进行了广泛的研究，但沙门氏菌与肠上皮和上皮先天免疫应答的相互作用在体内仍然不清楚。永生化上皮细胞系不反映复杂的细胞组成，功能分化，解剖组织和腔暴露的上皮在体内。我们在新生小鼠中新建立的口腔沙门氏菌感染模型首次开启了在适合遗传修饰的宿主中研究体内侵袭诱导的上皮刺激的可能性（Zhang et al.，2014）。该体内模型通过使用离体衍生的干细胞类器官来补充，以（i）表征沙门氏菌诱导的上皮先天免疫信号传导，（ii）评价感染诱导的上皮先天免疫刺激的下游效应，和（iii）分析细菌毒力因子及其对上皮先天免疫信号传导的干扰。我们期望所提出的实验提供了一个更好的理解的早期阶段的粘膜宿主对感染的反应，即肠上皮细胞和沙门氏菌在体内之间的相互作用。我们希望，更好地了解将促进新的战略，以防止或限制疾病的早期阶段的感染，并确定年龄依赖性因素的易感性的新生儿宿主侵袭性沙门氏菌感染的发展。

Salmonella is able to invade non-phagocytic intestinal epithelial cells followed by intracellular proliferation and transepithelial migration. The conservation of the responsible molecular effector molecules in human Salmonella isolates suggests a critical contribution of this step in the pathogenesis of infection. Although extensively studied in vitro, the interaction of Salmonella with the intestinal epithelium and the epithelial innate immune response has remained ill defined in vivo. Immortalized epithelial cell lines do not reflect the complex cell composition, functional differentiation, anatomical organisation and luminal exposure of the epithelium in vivo. Our newly established oral Salmonella infection model in neonate mice for the first time opens the possibility to investigate the invasion-induced epithelial stimulation in vivo in a suitable host amenable to genetic modification (Zhang et al., 2014). This in vivo model is complemented by the use of ex vivo derived stem cell organoids to (i) characterize the Salmonella-induced epithelial innate immune signaling, (ii) evaluate downstream effects of infection-induced epithelial innate immune stimulation and (iii) analyze bacterial virulence factors and their interference with epithelial innate immune signaling. We expect that the proposed experiments provide a better understanding of the early phase of the mucosal host response to infection, i.e. the interaction between the intestinal epithelium and Salmonella in vivo. We hope that a better understanding will facilitate the development of new strategies to prevent or restrict disease at an early stage of the infection and identify age-dependent factors underlying the susceptibility of the neonate host to invasive Salmonella infection.