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

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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.