IBR   13079
INSTITUTO DE BIOLOGIA MOLECULAR Y CELULAR DE ROSARIO
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Trypanosoma cruzi sirtuins as drug targets for Chagas Disease
Autor/es:
CARLA RITAGLIATI; VICTORIA LUCIA ALONSO; PAMELA CRIBB; ESTEBAN SERRA
Lugar:
Woods Hole, Massachusetts
Reunión:
Simposio; Molecular Parasitology Meeting; 2015
Institución organizadora:
Marine Biological Laboratory
Resumen:
Trypanosoma cruzi is the protozoan pathogen responsible for Chagas disease, which affects 8 million people and causes nearly 14,000 deaths worldwide. Current therapies rely on a very small number of drugs, most of which are inadequate because of their severe host toxicity and susceptibility to drug-resistance mechanisms. To determine efficient therapeutic alternatives, the identification of new biotargets is essential. Class III HDACs, sirtuins, are highly conserved from Archaea to higher eukaryotes, and they have been recently considered as promising targets for the development of new treatments for Chagas disease. We?ve performed the first characterization of T. cruzi sirtuins and we have constructed transgenic lines, which are useful for the screening of sirtuin inhibitors. TcSIR2RP1 is a cytoplasmic enzyme and TcSIR2RP3 localizes in the mitochondrion. When we overexpress TcSIR2RP1, the transgenic parasites differentiate to metacyclic trypomastigotes and infect mammalian cells more efficiently. In contrast, the overexpression of TcSIR2RP3 does not affect metacyclogenesis but modifies epimastigotes growth, TcSIR2RP3HA overexpressing epimastigotes have a slower decay, thus suggesting a pro-survival role of this protein, and the intracellular stage exhibits an increased proliferation rate. TcSIR2RP3 is involved in the response to oxidative stress; when overexpressed, parasites are less sensitive to H202 and Nifurtimox. The overexpression of both sirtuins protected the parasite from the effect of known sirtuin inhibitors.