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

• Grant number: 20/07870-4
• Support Opportunities: Research Projects - Thematic Grants
• Duration: June 01, 2021 - May 31, 2026
• Field of knowledge: Biological Sciences - Biochemistry - Biochemistry of Microorganisms
• Principal Investigator: Sergio Schenkman
• Grantee: Sergio Schenkman
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated researchers: Ana Claudia Trocoli Torrecilhas ; Fabíola Barbieri Holetz ; Nilmar Silvio Moretti
• Associated scholarship(s): 21/12515-1 - Oxidative stress response mechanisms in phosphorylation of eIF2± and AMPK in T. cruzi, BP.DD; 21/12527-0 - Characterization of protein kinases involved in the control of metabolism in Trypanosomatdes, BP.IC; 21/12883-0 - Characterization of protein quinases involved in the translation control, metabolism and extracellular vesicles secretion in trypanosomatides, BP.PD

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)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

SAENZ-GARCIA, JOSE L.; BORGES, BEATRIZ S.; SOUZA-MELO, NORMANDA; MACHADO, LUIZ V.; MIRANDA, JULIANA S.; PACHECO-LUGO, LISANDRO ALFONSO; MORETTI, NILMAR S.; WHELEER, RICHARD; SOARES MEDEIROS, LIA C.; DAROCHA, WANDERSON D.. rypanin Disruption Affects the Motility and Infectivity of the Protozoan Trypanosoma cruz. FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY, v. 11, JAN 7 2022. (18/09948-0, 20/07870-4)

VASCONCELOS, CAMILLA IOSHIDA; CRONEMBERGER-ANDRADE, A.; SOUZA-MELO, NORMANDA; MARICATO, JULIANA TERZI; XANDER, PATRICIA; BATISTA, WAGNER LUIZ; SOARES, RODRIGO PEDRO; SCHENKMAN, SERGIO; TORRECILHAS, ANA CLAUDIA. Stress Induces Release of Extracellular Vesicles by Trypanosoma cruzi Trypomastigotes. JOURNAL OF IMMUNOLOGY RESEARCH, v. 2021, SEP 24 2021. (19/15909-0, 20/07870-4, 17/02416-0)

DOS SANTOS MOURA, LEILA; SANTANA NUNES, VINICIUS; GOMES, ANTONIEL A. S.; SOUSA, ANA CAROLINE DE CASTRO NASCIMENTO; FONTES, MARCOS R. M.; SCHENKMAN, SERGIO; MORETTI, NILMAR SILVIO. Mitochondrial Sirtuin TcSir2rp3 Affects TcSODA Activity and Oxidative Stress Response in Trypanosoma cruzi. FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY, v. 11, NOV 11 2021. (14/03714-7, 20/07870-4, 18/09948-0, 15/22031-0)