Leishmania amazonensis-macrophage interactions: homeostatic changes associated with HSP70 overexpression in L. amazonensis cellular profile of leishmaniasis lesions effects of glyceraldehyde 3-phosphate dehydrogenase inhibitors

Abstract

Leishmaniasis is an endemic parasitosis, there is no vaccine for commercial use, there are reports of failures and resistance and side effects of therapeutic compounds, and is limited knowledge of host and parasite factors that influence pathogenesis. This project is divided into three subprojects: 1) homeostatic changes associated with HSP70 over expression in L. amazonensis. The chaperones HSPs (heat shock protein) are involved in protective responses to various stresses. The experimental approach for over expression is essential to test the hypothesis that HSPs are involved in parasite protection/ homeostasis and the identification of biological processes triggered by this protein. Our goal is to induce HSP70 over expression in promastigotes and evaluate virulence, infectivity and microenvironmental stress responses. 2) Cellular profile of leishmaniasis lesions. The study of intralesional cellular dynamics will allow the understanding of the mechanisms of macrophage phenotype modulation during the infection process. The aim is to study the cells taken from lesions of infected mice, and analyzing macrophage responses to classical activators and anti-Leishmania. 3) Inhibitor glyceraldehyde 3-phosphate dehydrogenase in infection control. The goal is to test the potential of synthetic inhibitors of glyceraldehyde 3-phosphate dehydrogenase, an enzyme important in the glycolytic pathway of trypanosomatids, in controlling L. amazonensis infection. Specifically we will evaluate the possible leishmanicidal activity of synthetic compounds in promastigotes, infected macrophages and susceptible mice. The data will reveal the involvement of HSP70 in the biological processes of the parasite, the profile of host cells ex vivo and the potential of synthetic inhibitors of the glyceraldehyde 3-phosphate dehydrogenase in infection control, enabling the identification of therapeutic targets and development of treatments already established for this pathology. (AU)