The Importance of Inflammatory Chemokine Receptors in The Immune Response To Leishmania Infections
Intracellular parasites of the genus Leishmania are responsible for a spectrum of human diseases. Theses range in severity from life-threatening to self resolving, but all pose significant global health concerns. Studies of the host response to leishmania infection have shown that both parasite- and host-factors contribute to leishmaniasis disease outcome. Among the factors of the host immune system employed to control parasite replication and spread are the chemokines. These small molecules interact specifically with g-protein coupled receptor molecules on target cell surfaces and this receptor/ligand interaction can result in numerous cellular functions including migration and activation of immune cells. In these studies I evaluate the relevance of certain chemokine receptors to the disease outcome of Leishmania major infection, and also I attempt to elucidate the mechanisms regulating expression of a crucial chemokine receptor, CXCR3. In the following chapters I report the results of my inquiries into the importance of certain chemokine receptors to the host response during cutaneous leishmaniasis, a comparison of the roles played by the chemokine receptor CXCR3 in distinct manifestations of leishmaniasis, as well as our detailed dissection of the mechanisms regulating this particular chemokine receptor in murine T cells.
In summary, we found that functional CXCR3 signaling is uniquely required for murine resistance to Leishmania major by recruiting IFN-gamma producing T cells to the site of infection. CXCR3-signaling was not found to be important in the response to experimental Leishmania donovani infection. Studies of CXCR3 induction by T cells both in vivo and in vitro demonstrate that T cells from L. major-resistant mice strains dramatically up-regulate CXCR3 upon activation or challenge while T cells from an L. major- susceptible strain fail to do so. Also, CD4+ T cells and CD8+ T cells differentially require the IFN-gamma/STAT1 signaling pathway for CXCR3 induction. These studies have improved our understanding of the role played by chemokine receptor-ligand pairs in anti-parasite immune responses. Also, these studies have clarified aspects of CXCR3 regulation relevant for the anti-leishmania response and therapies for CXCR3-mediated immunopathologies.
School:The Ohio State University
School Location:USA - Ohio
Source Type:Master's Thesis
Keywords:leishmania chemokine receptor cxcr3 t cell
Date of Publication:01/01/2008