Browsing Electronic Theses and Dissertations by Author "A. Clinton White, MD"
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ItemRegulation of innate immune responses to Leishmania braziliensis infection(2009-09-08) Diego A Vargas Inchaustegui; Lynn Soong, MD, PhD; Nigel Bourne, PhD; Kai Zhang, PhD (Texas Tech University); Janice J. Endsley, PhD; A. Clinton White, MDLeishmania braziliensis (Lb) is a protozoan parasite, and the causative agent of cutaneous (CL) and mucocutaneous (ML) leishmaniasis in South America. ML is a severe and disfiguring form of the disease, usually compromising mucosal tissues within the nose, mouth and pharynx. In humans, ML is characterized by excessive T and B cell responses to the parasite, which contribute to inflammation and tissue destruction. Since our understanding of how Lb parasites interact with dendritic cells (DCs) is limited, the present dissertation was aimed at studying the immune processes that take place during Lb infection. Our results have revealed three unique features of Lb infection. First, using a mouse model we showed that DCs can efficiently recognize, process and present parasite antigens to CD4+ T, cells initiating the development of protective immune responses. Specifically, Lb-infected DCs induced the proliferation of naïve CD4+ T cells and the production of IFN-γ and IL-17. Second, we demonstrated that interaction between pathogen recognition receptors and Lb parasites occurs both in vitro and in vivo, and that these interactions modify DC activation and infection outcome. We found that whereas the adaptor protein MyD88 was necessary for the establishment of a protective immune response against Lb infection, the absence of TLR2 did not increase mouse susceptibility to infection. Finally, by using a human peripheral blood mononuclear cell (PBMC) in vitro system for Lb infection, we evaluated the early innate immune events associated with infection. Our results showed that within PBMCs, monocytes were the target cell for Lb infection, resulting in the production of inflammatory chemokines. By comparing our human in vitro studies to the chemokine profile observed in CL and ML patients, we revealed a potential association between the magnitude of the inflammatory response and disease severity. Collectively, our studies have contributed to an advanced understanding of Lb pathogenesis, in particular the roles played by DCs and monocytes. Furthermore, our data has identified several molecules for future studies to better understand the host- and pathogen-associated mechanisms of pathology and disease control.