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Molecular basis of Trypanosoma cruzi infection: mechanisms and comparison of two phylogenetically distinct parasite lineages

Abstract

Trypanosoma cruzi, the agent of Chagas' disease, is an organism of great interest from the biological point of view. Although the transmission of the disease is controlled in countries of the Southern Cone, T. cruzi continues to be transmitted in many countries in Latin America and infection by this parasite, which affects 15-16 million people, represents a serious public health problem. Despite the fact that more than 90 years have elapsed since its discovery, T. cruzi infection is not well understood in various aspects. The aim of this project is to study, in a broad context, the process of infection by T. cruzi, a complex that includes phylogenetically distinct strains. To understand this complex, we will undertake a comparative analysis of parasite strains and clones belonging to the two major phylogenetic lineages (T. cruzi I and T. cruzi II), whose diversity has been revealed by our findings and of other research groups. The informations generated in our and other laboratories point to the importance of analyzing T. cruzi infection under this perspective. We will proceed our work aiming at the elucidation, at the molecular level, of the mechanisms of cell invasion, escape from the parasitophorous vacuole, intracellular development and persistence of the parasite in the mammalian host. An example of the diversity between T. cruzi I and T. cruzi II is the ability to invade mammalian cells in vitro, which is associated with the differential expression of surface glycoproteins and with activation of different signal transduction pathways. In addition to this diversity, among many others, there is the question of different developmental forms of the parasite invading host cells through distinct mechanisms. Metacyclic trypomastigotes, amastigotes and blood trypomastigotes express on their surface stage-specific molecules that confer properties for differential cellular interactions. The present initiative will contemplate all these points through experiments with the various infective forms or T. cruzi. We intend to go further by including in vivo and ex-vivo assays. The role of the different parasite molecules in infection will be analysed. The structure-function relationship of different molecules, defined so far for only a few of them, will be examined by sequencing the respective cloned genes, the generation of recombinant proteins for biological assays, in addition to the production of antibodies for diverse purposes. Different approaches will be employed for structural analysis of native molecules purified from the parasite. Included in this project is also the study of structure, organization and expression of genes coding for T. cruzi surface molecules implicated in the process of infection. These studies may bring new informations on the mechanisms of regulation of the expression of different genes and on the evolution of gene families. Our group, whose members have expertise in cell biology, molecular biology, immunology, confocal and electron microscopy, has been working for many years, in a very productive manner, in joint research programmes. Collaborations with other laboratories in Brazil and abroad will strengthen our team towards the accomplishment of the proposed project. (AU)

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