Subproject B6

Following oral infection with Toxoplasma gondii susceptible C57BL/6 mice develop a Th1-type immunopathology characterized as pan-ileitis. We have previously shown the role of pro-inflammatory cytokines, i.e. IL-12, IL-18, TNF-α, NO, and IFN-γ and/or effector molecules. Development of intestinal pathology also depends on the presence of the bacterial flora, i.e. E.coli. In the proposed studies we will investigate additional factors involved in the development of immunopathology using in-vitro-, ex-vivo-, and in-vivo-experiments. The importance of the bacterial flora points towards an early parasite-induced epithelial barrier defect. Therefore, the initial interaction between the parasite and epithelial cells in the intestine and neighboring innate lymphocytes (γδT cells, NK cells) will be investigated. In addition, we will determine which antigens (bacterial or parasitic) are recognized by antigen-presenting cells in the small intestine and whether these cells produce IL-23 that is known to induce Il-17-producing T (Th17) cells involved in inflammatory responses. Finally, the role and regulation of matrixmetalloproteinases, i.e. gelatinases, will be investigated. The proposed studies will clarify important aspects of the immunopathogenesis of oral infection with T. gondii and may assist in the development of new strategies for the treatment of inflammatory bowel diseases.