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DECODING THE ANTI-TRYPANOSOMA CRUZI ACTION OF HIV PEPTIDASE INHIBITORS USING EPIMASTIGOTES AS A MODEL
Autor
Afiliación
Universidade Federal do Rio de Janeiro (UFRJ). Instituto de Microbiologia Paulo de Góes (IMPG). Departamento de Microbiologia Geral. Laboratório de Investigação de Peptidases. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular e Doenças Endêmicas. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro (UFRJ). Instituto de Microbiologia Paulo de Góes (IMPG). Departamento de Microbiologia Geral. Laboratório de Investigação de Peptidases. Rio de Janeiro, RJ, Brasil / Universidade Federal do Rio de Janeiro. Instituto de Química. Programa de Pós-Graduação em Bioquímica. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro (UFRJ). Instituto de Microbiologia Paulo de Góes (IMPG). Departamento de Microbiologia Geral. Laboratório de Investigação de Peptidases. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular e Doenças Endêmicas. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro (UFRJ). Instituto de Microbiologia Paulo de Góes (IMPG). Departamento de Microbiologia Geral. Laboratório de Investigação de Peptidases. Rio de Janeiro, RJ, Brasil / Universidade Federal do Rio de Janeiro. Instituto de Química. Programa de Pós-Graduação em Bioquímica. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro (UFRJ). Instituto de Microbiologia Paulo de Góes (IMPG). Departamento de Microbiologia Geral. Laboratório de Investigação de Peptidases. Rio de Janeiro, RJ, Brasil.
Resumen en ingles
Background: Aspartic 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 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 most effective inhibitors, ritonavir, lopinavir and nelfinavir, also had
an anti-proliferative effect against different phylogenetic T. cruzi strains. The HIVPIs
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 pretreatment
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 Significance: The 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.
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