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GRK 1482 Jahrbuch 2011-2014

Abstract Although it has been demonstrated that the commensal gut microbi- ota is involved in the pathogenesis of chronic intestinal inflammation, the bacterial structures and mechanisms triggering disease patholo- gy remain unclear. Enterococcus faecalis, a member of the human gut microbiota, was shown to induce intestinal inflammation in a mouse model of experimental colitis. Here we show evidence for a prominent role of several bacterial virulence factors in mediating the interaction of Enterococcus faecalis with the host in the context of chronic intes- tinal inflammation. Introduction Inflammatory bowel diseases (IBD) are immune- mediated intestinal disorders characterized by chronic inflammation of the gastrointestinal tract. Several factors have been suggested to trigger the pathogenesis of IBD including genetic predisposi- tion [1] and environmental factors such as gut mi- crobiota. It has been demonstrated that the com- mensal gut microbiota is involved in disease patho- logy, but the mechanisms remain to be elucidated. Enterococcus faecalis is a commensal of the hu- man intestinal microbiota known for harboring se- veral putative virulence factors mediating its bac- terial pathogenicity. Though being commensals, enterococci are one of the leading causes for no- socomial infections, making their putative virulence factors an exemplary model to analyze structure- function relationships in interaction with the host. Commensal E. faecalis induced intestinal inflam- mation in the IL-10 deficient (IL-10-/-) mouse model of experimental colitis [2]. Among the mul- tiplicity of virulence factors produced by E. faecalis, the secreted zinc-dependent protease gelatinase E (GelE) was shown to contribute to intestinal inflam- mation in mouse models of experimental colitis [3,4]. However, since a loss of GelE did not result in total diminution of intestinal inflammation, we tar- get two additional bacterial structures mediating E. faecalis pathogenicity: The enterococcal polysaccharide antigen (epa) lo- cus has been previously described as a virulence- relevant gene cluster. We generated ∆epaB and ∆epaB∆gelE isogenic mutant strains from the OG1RF strain. We identified cell-wall lipoproteins from E. faecalis to be important for the TLR2-mediated activation of bone marrow-derived dendritic cells and genera- ted lipoprotein-deficient (∆lgt) and lipoprotein-GelE deficient (∆lgt∆gelE) double mutant strains from OG1RF. To investigate structure-based functions, these E. faecalis mutant strains were characterized in animal models of IBD including monoassociated IL-10-/- mice for colitis and TNF∆ARE/+ mice for ileitis. Sören Ocvirk (M.Sc.) Nutrition and Immunology PhD 2/2 Impact of Enterococcus faecalis in the regulation of chronic intestinal inflammation: structure-function relationship in microbe-host interaction PhD FELLOWS Page 38 | GRK Progress Report 2011-2014