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
• Start date: June 01, 2021
• End date: May 31, 2026
• Field of knowledge: Biological Sciences - Biochemistry - Biochemistry of Microorganisms
• Principal Investigator: Ana Claudia Trocoli Torrecilhas
• Grantee: Ana Claudia Trocoli Torrecilhas
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Pesquisadores principais: Sergio Schenkman
• Associated researchers: Ana Claudia Trocoli Torrecilhas ; Fabíola Barbieri Holetz ; Nilmar Silvio Moretti
• Associated scholarship(s): 24/03874-6 - Bioinformatics analysis of RNASeq and Nanopore data from samples of Leishmania evolutionary forms, BP.TT; 22/15997-0 - The role of arginine transport in the stress response and differentiation of Trypanosoma cruzi, BP.IC; 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

(14)

(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)

MULLER DE BARROS, ROSANGELA APARECIDA; TORRECILHAS, ANA CLAUDIA; MORAES MARCIANO, MARIA APARECIDA; MAZUZ, MONICA LESZKOWICZ; PEREIRA-CHIOCCOLA, VERA LUCIA; FUX, BLIMA. Toxoplasmosis in Human and Animals Around the World. Diagnosis and Perspectives in the One Health Approach. Acta Tropica, v. 231, p. 18-pg., 2022-04-25. (20/07870-4, 19/15909-0)

MARCELINO, TIAGO DE PAULA; FALA, ANGELA MARIA; SILVA, MATHEUS MONTEIRO DA; SOUZA-MELO, NORMANDA; MALVEZZI, AMARANTA MUNIZ; KLIPPEL, ANGELICA HOLLUNDER; ZOLTNER, MARTIN; PADILLA-MEJIA, NORMA; KOSTO, SAMANTHA; FIELD, MARK C.; et al. Identification of inhibitors for the transmembrane Trypanosoma cruzi eIF2α kinase relevant for parasite proliferation. Journal of Biological Chemistry, v. 299, n. 7, p. 18-pg., 2023-07-01. (17/02496-4, 20/07870-4, 19/15909-0, 14/50897-0, 20/02006-0, 17/02416-0)

KOZELA, EWA; MENEGHETTI, PAULA; REGEV-RUDZKI, NETA; TORRECILHAS, ANA CLAUDIA; PORAT, ZIV. Subcellular particles for characterization of host-parasite interactions. Microbes and Infection, v. 26, n. 7, p. 10-pg., 2024-09-05. (20/07870-4, 19/15909-0)

CORTES-SERRA, NURIA; GUALDRON-LOPEZ, MELISA; PINAZO, MARIA-JESUS; TORRECILHAS, ANA CLAUDIA; FERNANDEZ-BECERRA, CARMEN. Extracellular Vesicles in Trypanosoma cruzi Infection: Immunomodulatory Effects and Future Perspectives as Potential Control Tools against Chagas Disease. JOURNAL OF IMMUNOLOGY RESEARCH, v. 2022, p. 11-pg., 2022-08-17. (20/07870-4, 19/15909-0)

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)

MADEIRA, RAFAEL PEDRO; MENEGHETTI, PAULA; LOZANO, NICHOLY; NAMIYAMA, GISLENE M.; PEREIRA-CHIOCCOLA, VERA LUCIA; TORRECILHAS, ANA CLAUDIA. Exploring Peripheral Blood-Derived Extracellular Vesicles as Biomarkers: Implications for Chronic Chagas Disease with Viral Infection or Transplantation. MICROORGANISMS, v. 12, n. 1, p. 18-pg., 2024-01-01. (20/07870-4, 19/15909-0)

SILVA, MICHEL AUGUSTO; IZIDORO, MARIO AUGUSTO; ARICO, MIRELLA; JULIANO, LUIZ; SCHENKMAN, SERGIO. The effect of nutritional and oxidative stress on the metabolome of Trypanosoma cruzi. Molecular Microbiology, v. 122, n. 5, p. 16-pg., 2024-05-30. (20/07870-4, 21/12515-1)

MENEGHETTI, PAULA; KOZELA, EWA; ALFANDARI, DANIEL; KARAM, PAULA ABOU; PORAT, ZIV; XANDER, PATRICIA; REGEV-RUDZKI, NETA; SCHENKMAN, SERGIO; TORRECILHAS, ANA CLAUDIA. Trypanosoma Cruzi G and Y Strains' Metacyclic Trypomastigote Sheds Extracellular Vesicles and Trigger Host-Cell Communication. Cell Biology International, v. N/A, p. 22-pg., 2025-06-02. (20/07870-4)

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)

SILVA, RAFAEL DE FREITAS E; BASSI, GABRIELA; CAMARA, NIELS OLSEN SARAIVA; MORETTI, NILMAR SILVIO. Sirtuins: Key pieces in the host response to pathogens' puzzle. Molecular Immunology, v. 160, p. 11-pg., 2023-07-10. (18/09948-0, 20/07870-4, 22/03075-0)

REGEV-RUDZKI, NETA; MICHAELI, SHULAMIT; TORRECILHAS, ANA CLAUDIA. Editorial: Extracellular Vesicles in Infectious Diseases. FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY, v. 11, p. 3-pg., 2021-07-01. (20/07870-4, 19/15909-0)

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)

DE LIMA, VERONICA A.; NUNES, JOAO P. S.; ROSA, DANIELA S.; FERREIRA, RODRIGO; OLIVA, MARIA L. V.; ANDREATA-SANTOS, ROBERT; DUARTE-BARBOSA, MARCIA; JANINI, LUIZ M. R.; MARICATO, JULIANA T.; AKAMATSU, MILENA A.; et al. Development and characterization of a multimeric recombinant protein using the spike protein receptor binding domain as an antigen to induce SARS-CoV-2 neutralization. IMMUNITY INFLAMMATION AND DISEASE, v. 12, n. 7, p. 16-pg., 2024-07-01. (20/07870-4)

XANDER, PATRICIA; GONCALVES, MARIANA; TORRECILHAS, ANA C.. Extracellular vesicles released by Trypanosoma cruzi and Leishmania spp.: protozoan parasite-host interaction mechanism. CURRENT OPINION IN PHYSIOLOGY, v. 43, p. 6-pg., 2025-03-01. (19/15909-0, 20/07870-4, 19/21614-3)