The function of factor X and PAR-2 in the early immune response against Leishmania major

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The Infection of susceptible and resistant mice strains with Leishmania major is a model disease for natural resistance and the development of Th2- or Th1-cells.Our focus lies on the events at the site of infection. We pursue the hypothesis that Th-cell differentiation in the lymph node is crucially influenced by signals from the early, tightly regulated inflammatory micromilieu in the infected skin. So called danger signals produced in the infected skin influence the function of antigen presenting cells prior to their migration to the lymph node and the subsequent interaction with T-cells in the lymph node via third signals.Using a genome wide characterization, we found several local tissue signals which are early and differentially expressed between susceptible and resistant mice. Remarkably, the expression of several known Th1-inducing cytokines was temporally restricted to the first two days of infection, coinciding with the time frame during which the T-cell response is determined. One important source are keratinocytes. Due of their high number, they are able to produce sufficient amounts of cytokines. One of the few genes more highly expressed in susceptible mice is the chemokine CXCL11. It causes a Th2 response and higher parasite titers when injected in resistant C57BL/6 mice, but its local neutralization did not cause a Th1 response in BALB/c mice.Therefore we have focused again on potential Th1-inducing signals. We had previously focused on genes already implied in Th1 differentiation. We now have widened our scope as we had also found higher expression of coagulation factor X (FX) in the skin of resistant C57BL/6 mice. In mice of resistant background which are deficient for a known receptor of FX, i.e. protease-activated receptor 2 (PAR-2), we then observed higher parasite titers and a Th2 response. Since the coagulatory and immune systems influence each other and because PAR-2 and FX probably play a key role in this, we now want to further investigate these findings.Thus, the goal of this project is to unravel the mechanisms by which PAR-2 contributes to resistance and the relevance of FX and other PAR-2 agonists in this process. Moreover, we want to establish whether other factors of the coagulation system are involved in the Th1/Th2 immune response and whether the coagulation system is a pharmacological target in leishmaniasis and other infections.We expect further insights in both the pathophysiology of leishmaniasis as well as in general mechanisms of Th-cell differentiation, all in context of the interdependence of the coagulatory system and inflammation. The results may facilitate new therapeutic approaches in other Th1- or Th2-dependent inflammations.