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Ecto-nucleoside triphosphate diphosphohydrolases (NTPDases) are enzymes located on the surface of the <i>T. cruzi</i> plasma membrane, which hydrolyze a wide range of tri-/-diphosphate nucleosides. In this work, we used previously developed genetically modified strains of <i>Trypanosoma cruzi</i> (<i>T. cruzi</i>), hemi-knockout (KO +/−) and overexpressing (OE) the <i>TcNTPDase-1</i> gene to evaluate the parasite infectivity profile in a mouse model of acute infection (<i>n</i> = 6 mice per group). Our results showed significantly higher parasitemia and mortality, and lower weight in animals infected with parasites OE <i>TcNTPDase-1</i>, as compared to the infection with the wild type (WT) parasites. On the other hand, animals infected with (KO +/−) parasites showed no mortality during the 30-day trial and mouse weight was more similar to the non-infected (NI) animals. In addition, they had low parasitemia (45.7 times lower) when compared with parasites overexpressing <i>TcNTPDase-1</i> from the hemi-knockout (OE KO +/−) group. The hearts of animals infected with the OE KO +/− and OE parasites showed significantly larger regions of cardiac inflammation than those infected with the WT parasites (<i>p</i> < 0.001). Only animals infected with KO +/− did not show individual electrocardiographic changes during the period of experimentation. Together, our results expand the knowledge on the role of NTPDases in <i>T. cruzi</i> infectivity, reenforcing the potential of this enzyme as a chemotherapy target to treat Chagas disease (CD).