Host-pathogen interaction in a novel in vivo model of enteropathogenic Escherichia coli (EPEC) infection

肠致病性大肠杆菌（EPEC）是世界范围内人类婴儿腹泻的重要病原体，与发展中国家幼儿死亡的高归因风险相关。尽管在过去的几十年里，人们在体外共培养模型中广泛研究了EPEC与哺乳动物细胞之间的相互作用，但由于缺乏合适的小动物感染模型，EPEC在体内更复杂的肠道组织环境中诱导疾病的机制仍然不清楚。我们最近在新生小鼠中建立了一种新的体内感染模型，该模型显示出人中EPEC感染的许多特征，例如年龄依赖性易感性、典型的附着和消失（A/E）病变的形成以及细菌毒力因子例如编码的3型分泌系统（T3 SS）的关键作用（Dupont等人，2016）。利用这种新的感染模型，本研究建议的目的是表征细菌毒力因子的生物学作用，并确定宿主因素，确定这种非侵入性小肠病原体感染的易感性。具体而言，拟议项目涉及以下三个问题： 描述新生儿宿主肠道感染的粘膜免疫反应。（二） 分析细菌效应分子在宿主-微生物相互作用中的作用。（三） 确定决定宿主对细菌挑战的敏感性的宿主因素。拟议的工作预计将显着扩大我们对EPEC逃避宿主的抗菌防御和诱导婴儿肠道疾病的机制的认识。它还将有助于更好地了解保护性宿主反应，并可能最终有助于制定未来的预防和治疗策略，以减少与EPEC感染相关的发病率和死亡率。

Enteropathogenic Escherichia coli (EPEC) represent an important causative agent of human infant diarrhea worldwide and are associated with a high attributable risk of death in young infants in developing countries. Whereas the interaction between EPEC and mammalian cells has been extensively studied in co-culture models in vitro over the last decades, the mechanisms employed by EPEC to induce disease in the more complex intestinal tissue environment in vivo have remained ill-defined due to the lack of a suitable small animal infection model. We have recently established a new in vivo infection model in neonate mice that displays many of the characteristics of EPEC infection in humans, such as the age-dependent susceptibility, the formation of typical attachment and effacement (A/E) lesions and the critical role of bacterial virulence factors such as the encoded type 3 secretion system (T3SS) (Dupont et al., 2016). Exploiting this novel infection model, the present research proposal aims at characterizing the biological role of bacterial virulence factors and identifying host factors that determine the susceptibility to infection with this non-invasive small intestinal pathogen. Specifically, the proposed project addresses the three following issues:(i) Characterizing the mucosal immune response to enteric infection of the neonate host.(ii) Analyzing the role of bacterial effector molecules during host-microbial interaction.(iii) Identifying host factors that determine the host susceptibility to bacterial challenge.The proposed work is expected to significantly expand our knowledge of the mechanism employed by EPEC to evade the antimicrobial defense of the host and induce enteric disease in infants. It will also help to better understand the protective host response and might ultimately help to develop future preventive and therapeutic strategies to reduce the morbidity and mortality associated with EPEC infection in small children.