Between vigilance and tolerance: Innate immune signaling at the intestinal epithelium

• Applicant: Professor Dr. Mathias Walter Hornef
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2012 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 221043826

Only one single layer of epithelial cells separates the densely colonized and environmentally exposed intestinal lumen from the largely sterile subepithelial tissue. Together with the overlaying mucus and the subepithelial mucosal immune system the epithelium has evolved to maintain homeostasis in the presence of the enteric microbiota. On the other hand, it provides rapid and efficient antimicrobial host defence in the event of infection with enteropathogenic bacteria. Increasing evidence suggests that both, homeostasis and antimicrobial host defence rely on epithelial signaling pathways induced by innate immune receptors such as Toll-like receptors (TLR), Nod like receptors (NLR) or helicases. However, innate immune receptor ligands are similarly produced by commensal and enteropathogenic bacteria and the mechanisms that prevent inflammation and facilitate homeostatic signaling in the presence of the enteric microbiota but allow rapid immune activation in the event of microbial infection are still ill-defined. The present research application aims at a better understanding of the molecular processes underlying epithelial innate immune recognition, enteric antimicrobial host defence and mucosal homeostasis with particular emphasis on the fetal-postnatal transition and the molecular processes that regulate the epithelial host-microbial interaction. The research project addresses the following three issues:(i) Characterization of modifying factors and downstream effects of postnatal epithelial tolerance. (ii) Identification of negative regulatory mechanisms of innate immune recognition and signaling at the adult epithelium.(iii) Analysis of the molecular processes that terminate pro-inflammatory innate immune signaling after transient challenge.The results are expected to facilitate a better understanding of the processes involved to establish and maintain the intestinal mucosal barrier and prevent the development of symptomatic mucosal disease such as inflammatory bowel disease (IBD) or necrotizing enterocolitis (NEC).

• DFG Programme: Research Grants