Abstract
BackgroundAspartic peptidase inhibitors have shown antimicrobial action against distinct microorganisms. Due to an increase in the occurrence of Chagas' disease/AIDS co-infection, we decided to explore the effects of HIV aspartic peptidase inhibitors (HIV-PIs) on Trypanosoma cruzi, the etiologic agent of Chagas' disease.Methodology and Principal FindingsHIV-PIs presented an anti-proliferative action on epimastigotes of T. cruzi clone Dm28c, with IC50 values ranging from 0.6 to 14 µM. The most effective inhibitors, ritonavir, lopinavir and nelfinavir, also had an anti-proliferative effect against different phylogenetic T. cruzi strains. The HIV-PIs induced some morphological alterations in clone Dm28c epimastigotes, as reduced cell size and swollen of the cellular body. Transmission electron microscopy revealed that the flagellar membrane, mitochondrion and reservosomes are the main targets of HIV-PIs in T. cruzi epimastigotes. Curiously, an increase in the epimastigote-into-trypomastigote differentiation process of clone Dm28c was observed, with many of these parasites presenting morphological alterations including the detachment of flagellum from the cell body. The pre-treatment with the most effective HIV-PIs drastically reduced the interaction process between epimastigotes and the invertebrate vector Rhodnius prolixus. It was also noted that HIV-PIs induced an increase in the expression of gp63-like and calpain-related molecules, and decreased the cruzipain expression in epimastigotes as judged by flow cytometry and immunoblotting assays. The hydrolysis of a cathepsin D fluorogenic substrate was inhibited by all HIV-PIs in a dose-dependent manner, showing that the aspartic peptidase could be a possible target to these drugs. Additionally, we verified that ritonavir, lopinavir and nelfinavir reduced drastically the viability of clone Dm28c trypomastigotes, causing many morphological damages.Conclusions and SignificanceThe results contribute to understand the possible role of aspartic peptidases in T. cruzi physiology, adding new in vitro insights into the possibility of exploiting the use of HIV-PIs in the clinically relevant forms of the parasite.
Highlights
To determine whether human immunodeficiency virus (HIV) PIs would be effective against strains belonging to different T. cruzi lineages, the epimastigote forms of Y (TCII), INPA 4167 (TCIV) and CL Brener (TcVI) strains were submitted to the treatment with the three most efficacious inhibitors for clone Dm28c, i.e., ritonavir, lopinavir and nelfinavir
We began to study the implications of different HIV aspartic peptidase inhibitors (HIV PIs) on the cell biology of T. cruzi, and simultaneously to explore the possible roles of aspartic peptidases in the life cycle of this parasite
HIV PIs are the only aspartic peptidase inhibitors licensed for use in humans, in AIDS
Summary
Trypanosoma cruzi, the etiologic agent of Chagas’ disease, infects 8 million people in Latin America and has a wide distribution in these countries [3]. The recent influx of immigrants from endemic countries have turned Chagas’ disease into a major health problem in the United States of America, Canada and in many parts of Europe, where an increasing number of infected individuals has been identified. Due to an increase in the occurrence of Chagas’ disease/AIDS co-infection, we decided to explore the effects of HIV aspartic peptidase inhibitors (HIV-PIs) on Trypanosoma cruzi, the etiologic agent of Chagas’ disease. Methodology and Principal Findings: HIV-PIs presented an anti-proliferative action on epimastigotes of T. cruzi clone Dm28c, with IC50 values ranging from 0.6 to 14 mM. The hydrolysis of a cathepsin D fluorogenic substrate was inhibited by all HIV-PIs in a PLOS ONE | DOI:10.1371/journal.pone.0113957 December 2, 2014
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