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Influence of the cholesteryl ester transfer protein (CETP) expression on experimental cutaneous leishmaniasis.


Leishmaniases diseases caused by protozoan of the genus Leishmania manifest as tegumentary or visceral leishmaniasis. In leishmaniases, studies focusing on immune response are predominant, but we believe that nonspecific elements outside the immune system play an important role in the development of infection. Since in the development of Leishmania (L.) infantum infection, which causes visceral leishmaniasis (VL), the vast majority of those infected do not develop the active disease, we believe that factors other than the adaptive immune response should have an important role in the evolution of the infection. Also in the different forms of tegumentary leishmaniasis the lesion does not result directly from susceptibility to infection but as consequence of persistent immune response and inflammation. In this way, we started studies of non-specific factors including lipids.In the literature, studies demonstrate the importance of cholesterol and its fractions in VL both in the internalization of Leishmania by the host cell, in the energetic metabolism of the parasite, and in the susceptibility to the disease. The association of plasma lipoprotein levels and polymorphisms in the gene encoding lipoprotein lipase with the susceptibility to the development of active LV was demonstrated by us in a case-control study with individuals from the endemic area for VL.Despite advances in studies on lipid participation in parasite metabolism and in the interaction of Leishmania and host cells in VL, no studies of alterations of serum lipoprotein levels in cutaneous leishmaniasis are known nor whether changes in the metabolic pathway of lipoproteins would influence infection. Thu, in the research proposed here we intend to study the impact of cholesterylester transfer protein (CETP), an important component of reverse cholesterol transport, on L. (L.) amazonensis infection, a dermotropic species. The proposal is based on recent findings in the literature, showing the importance of CETP in the evolution of infectious conditions with an anti-inflammatory role in experimental endotoxemia and sepsis and the knowledge that the lesion in tegumentary leishmaniasis is predominantly consequence of the persistent inflammatory process . In this context, we propose to investigate the impact of CETP expression on infection development and the inflammatory response in an experimental model of cutaneous leishmaniasis. Transgenic mice for human CETP compared to their wild-type C57BL6 / J line controls will be infected by Leishmania (L.). amazonensis, a species that causes cutaneous leishmaniasis. Parasitism will be compared between groups of animals and correlated with inflammatory markers. Modulation of infection in the presence and absence of CETP will also be evaluated in culture of macrophages infected with L. (L.) amazonensis promastigotes in the presence and absence of recombinant human CETP (exogenous CETP) and in bone marrow derived macrophages from transgenic mice to human CETP (endogenous CETP). Parasitism and the release of cytokines, chemokines, nitric oxide and the gene expression of PPAR³, TLR2 and TLR4 receptors and growth factors will be evaluated. (AU)