Mechanisms of trypanosomatid adaptation to hosts through the control of transcription, protein synthesis and secretion of extracellular vesicles

Abstract

Parasitic protozoa of Trypanosoma and Leishmania species, respectively agents of Chagas disease and leishmaniasis, control their gene expression mainly through post-translational mechanisms. This is due to the selection of mRNAs that will be translated in each environment in which the parasites are located. During the passage from one host to another, changes occur in the availability of nutrients, temperature, oxidation state, and pH, among others, which induce alterations in protein synthesis, and in the differential accumulation of mRNA in various kinds of granules. At the same time, it is noted that the parasites release part of their protein components, mainly in the form of membrane vesicles, and then translate proteins required to the new condition. Our group has been investigating for some years how protein synthesis in trypanosomes is regulated when subjected to nutritional stresses. More recently we have sought to understand how this protein release would be occurring under certain stress conditions. In this new thematic project, we bring together three independent research groups that together will seek to understand in greater detail the mechanisms involved in the processes of: a) control of transcription, translation and the formation of mRNA granules; b) degradation of endogenous proteins induced by various environmental changes; and c) release of extracellular vesicles and their role in interaction with the host. For this, we will use Trypanosoma cruzi and Leishmania as model of study. Our studies will focus on the role of protein kinases that phosphorylate translation initiation factor 2 and 5 (eIF2, and eIF4E) main control points of protein synthesis in response to stress, the formation of RNA granules, the role of mRNA acetylation in the regulation of RNA stability and protein efficiency. The studies about transcription regulation will focus on the function of protein acetylation in the control of translation and transcription. We will investigate the role of AMP-dependent protein kinase (AMPK) in the control of autophagy and the energetic metabolism, and of deubiquitinases in the mechanism of secretion and release of extracellular vesicles related to interaction of the parasite with the host. These studies will allow us to better understand the mechanisms of adaptation of these parasites in their hosts and to contribute to a better understanding of the diseases caused by them. They will also contribute to the identification of potential drug targets for further validation. (AU)