The role of fatty acid-binding proteins in the macrophage infection by Leishmania: a potential target for new drugs against leishmaniasis

Abstract

Leishmaniasis is an infection caused by protozoa of the genus Leishmania. While parasitizing the vertebrate host, amastigote forms occupy the parasitophorous vacuole of macrophages. Although the factors that ensure parasite survival in this microenvironment are poorly understood, it has been recently proposed that amastigotes incorporate fatty acids for amino acid biosynthesis in a very efficient way. Therefore, it is reasonable to assume the existence of a mechanism that controls the traffic of fatty acids in infected macrophages. It is known that fatty acid-binding proteins (FABPs), abundant in the cytoplasm of macrophages and adipocytes, transport fatty acids to different cell compartments and play a crucial role in the regulation of cellular metabolism and inflammatory response. Besides, recent studies have demonstrated that macrophage FABP type 4 (FABP4) transcript levels are increased after Leishmania infection. Based on these findings, this project aims to determine whether different Leishmania species of national epidemiological importance are capable of modulating the activity of the host cell FABP4, as an adaptive strategy to ensure access to nutrients and survival. Biochemical and molecular tools, such as FABP4 knockdown and treatment with FABP4 inhibitors, combined with transgenic mice infections, will allow the characterization of the FABP4 role during macrophage infection with Leishmania. Later, leishmanicidal effect of molecules capable of interfering with the cell signaling pathway mediated by the FABPs will be evaluated in an attempt to identify a drug candidate for leishmaniasis treatment. (AU)