Project A02

Age-dependent intestinal epithelial determinants of infections with enteropathogenic Escherichia coli and Campylobacter jejuni

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Prof. Dr. Sina Bartfeld & Prof. Dr. Cynthia Sharma

 

Diarrhoea is still a major cause of infant death. Enteropathogenic Escherichia coli (EPEC) is the deadliest and Campylobacter jejuni the most common causative agent of diarrhoea in young children. Both cause a particularly strong pathology in very young children, the reason for which remains enigmatic. While likely several different factors contribute to this process, in the current project we aim to explore epithelia-intrinsic determinants involved in this age-specific pathology. Similar to the lung and skin, the gastrointestinal epithelium provides a physical barrier to infectious agents and must initiate appropriate immune responses. Dysregulation of these processes causes increased susceptibility to infection as well as inflammatory diseases. However, knowledge about the development of the physical and immune barrier functions of the intestinal epithelium is scarce. Here, we will focus on molecular decision points relevant to the initial contact of EPEC and C. jejuni with heterogeneous epithelial cell (sub)types of the immature or mature distal small intestine. We will use stem cell-derived human organoids from neonate or adult patients to model age-specific barrier function during EPEC or C. jejuni infection. For this, we will use an existing biobank of organoids covering the adult GI tract and further expand our biobank of organoids from human term or preterm-born neonates. Upon establishing infection conditions in these models, we aim to identify and characterise molecular decision points that determine the switch from initial contact to established infections in an age-dependent manner. For example, it is largely unknown whether EPEC and C. jejuni target a specific epithelial cell subtype. For the zoonotic pathogen C. jejuni, disease development in the human host seems to additionally depend on the invasion of the intestinal epithelial lining. However, the molecular mechanisms of C. jejuni invasion, the fate of intracellular bacteria, and the potential contribution to the disease development remain unclear. We hypothesise that currently unknown age-dependent differences in site-specific intestinal cellular heterogeneity contribute to the initiation of infection. Using scRNA-seq, we aim to identify potential target cell (sub)types that promote or restrict adherence and/or internalisation by EPEC and C. jejuni. We will investigate underlying molecular mechanisms that mediate age-dependency of these gastrointestinal bacterial infections. In the future, we aim to understand which factors shape the age-dependent epithelial determinants and how they can be exploited for therapy development.