The role of eIF2 phosphorylation and sirtuins in the multiplication and differentiation of intracellular Trypanosoma cruzi

• Grant number: 14/01577-2
• Support type: Scholarships in Brazil - Doctorate
• Effective date (Start): May 01, 2014
• Effective date (End): March 31, 2018
• Field of knowledge: Biological Sciences - Biochemistry - Biochemistry of Microorganisms
• Principal researcher: Sergio Schenkman
• Grantee: Fabrício Castro Machado
• Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 11/51973-3 - Cell signaling mechanism of Trypanosoma in response to nutritional alterations and genotoxic agents, AP.TEM

Abstract

Trypanosoma cruzi, the protozoan that causes Chagas disease, proliferates inside mammalian cells as amastigotes. Through signs not yet known, the parasite grows and differentiates into tripomastigote form, which does not proliferate but can circulate in the bloodstream, invade new cells or transmit the infection to other hosts. To understand the mechanisms that control the parasite proliferation, our group studies how environmental changes interfere with their protein synthesis. We showed that phosphorylation of the alpha subunit of translation initiation factor elf2 (eIF2±) by specific protein kinases is required for differentiation of form epimastigotes that proliferates in the digestive tract of the insect vector to metacyclic that invade host cells. We also found that the knockout eIF2± kinase (TcK2) blocks the differentiation, but unexpectedly causes an increase of reactive oxygen species (ROS) by inhibiting growth. On the other hand, we noticed that the overexpression of a mitochondrial sirtuin, which is an enzyme capable of removing acetyl groups of lysines of proteins, activates various metabolic enzymes, causing a reduction in ROS levels with increased growth rate. In this PhD project we intend to assess how the absence of TcK2 and overexpression of the sirtuin cause changes in levels of ROS and if these modifications affect the growth and differentiation of intracellular forms of T. cruzi.

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)

CASTRO MACHADO, FABRICIO; BITTENCOURT-CUNHA, PAULA; MALVEZZI, AMARANTA MUNIZ; ARICO, MIRELLA; RADIO, SANTIAGO; SMIRCICH, PABLO; ZOLTNER, MARTIN; FIELD, MARK C.; SCHENKMAN, SERGIO. EIF2 alpha phosphorylation is regulated in intracellular amastigotes for the generation of infectiveTrypanosoma cruzitrypomastigote forms. Cellular Microbiology, v. 22, n. 11 JUL 2020. Web of Science Citations: 0.

MACHADO, FABRICIO CASTRO; FRANCO, CAIO HADDAD; DOS SANTOS NETO, JOSE VITORINO; DIAS-TEIXEIRA, KARINA LUIZA; MORAES, CAROLINA BORSOI; LOPES, ULISSES GAZOS; AKTAS, BERTAL HUSEYIN; SCHENKMAN, SERGIO. Identification of di-substituted ureas that prevent growth of trypanosomes through inhibition of translation initiation. SCIENTIFIC REPORTS, v. 8, MAR 20 2018. Web of Science Citations: 1.

LEANDRO DE JESUS, TERESA CRISTINA; NUNES, VINICIUS SANTANA; LOPES, MARIANA DE CAMARGO; MARTIL, DAIANA EVELIN; IWAI, LEO KEI; MORETTI, NILMAR SILVIO; MACHADO, FABRICIO CASTRO; DE LIMA-STEIN, MARIANA L.; THIEMANN, OTAVIO HENRIQUE; ELIAS, MARIA CAROLINA; JANZEN, CHRISTIAN; SCHENKMAN, SERGIO; CHAGAS DA CUNHA, JULIA PINHEIRO. Chromatin Proteomics Reveals Variable Histone Modifications during the Life Cycle of Trypanosoma cruzi. JOURNAL OF PROTEOME RESEARCH, v. 15, n. 6, p. 2039-2051, JUN 2016. Web of Science Citations: 12.