Abstract
Background Trypanosoma cruzi is the etiological agent of Chagas' disease. During the parasite life cycle, many molecules are involved in the differentiation process and infectivity. Peptidases are relevant for crucial steps of T. cruzi life cycle; as such, it is conceivable that they may participate in the metacyclogenesis and interaction with the invertebrate host.Methodology/Principal FindingsIn this paper, we have investigated the effect of the calpain inhibitor MDL28170 on the attachment of T. cruzi epimastigotes to the luminal midgut surface of Rhodnius prolixus, as well as on the metacyclogenesis process and ultrastructure. MDL28170 treatment was capable of significantly reducing the number of bound epimastigotes to the luminal surface midgut of the insect. Once the cross-reactivity of the anti-Dm-calpain was assessed, it was possible to block calpain molecules by the antibody, leading to a significant reduction in the capacity of adhesion to the insect guts by T. cruzi. However, the antibodies were unable to interfere in metacyclogenesis, which was impaired by the calpain inhibitor presenting a significant reduction in the number of metacyclic trypomastigotes. The calpain inhibitor also promoted a direct effect against bloodstream trypomastigotes. Ultrastructural analysis of epimastigotes treated with the calpain inhibitor revealed disorganization in the reservosomes, Golgi and plasma membrane disruption.Conclusions/SignificanceThe presence of calpain and calpain-like molecules in a wide range of organisms suggests that these proteins could be necessary for basic cellular functions. Herein, we demonstrated the effects of MDL28170 in crucial steps of the T. cruzi life cycle, such as attachment to the insect midgut and metacyclogenesis, as well as in parasite viability and morphology. Together with our previous findings, these results help to shed some light on the functions of T. cruzi calpains. Considering the potential roles of these molecules on the interaction with both invertebrate and vertebrate hosts, it is interesting to improve knowledge on these molecules in T. cruzi.
Highlights
Chagas’ disease is a neglected tropical disease, which remains a major health problem in Latin America
The first 15 hits all corresponded to calcium-dependent cysteine peptidases and had their theoretical molecular mass determined, and 4 out of these 15 homologues presented a molecular mass around 80 kDa: XP_ 816697.1 (78.3 kDa), XP_803757.1 (80.8 kDa), XP_820102.1 (82.4 kDa) and XP_816696.1 (82.6 kDa), which supports the recognition of T. cruzi 80 kDa calpain by the anti-Dm-calpain antibody [7]
We demonstrated that MDL28170 inhibited T. cruzi adhesion to the insect gut, arrested the metacyclogenesis process, reduced the bloodstream trypomastigote viability and promoted significant ultrastructural effects on reservosomes and Golgi of epimastigote forms
Summary
Chagas’ disease is a neglected tropical disease, which remains a major health problem in Latin America. The adhesion to the luminal midgut surface of the insect appears to be necessary for the metacyclogenesis, but there is a general lack of information about which molecules are implicated in this process [3,4]. In this context, peptidases, a class of hydrolytic enzymes responsible for breaking peptide bonds, has attracted the attention of our research group because of their role in several crucial steps of the life cycle of the trypanosomatid parasites [5]. Peptidases are relevant for crucial steps of T. cruzi life cycle; as such, it is conceivable that they may participate in the metacyclogenesis and interaction with the invertebrate host
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