Virulence factors of Trypanosoma cruzi: who is who?

Osório, Luís; Ríos, Isabel; Gutiérrez, Bessy; González, Jorge

doi:10.1016/j.micinf.2012.09.003

Cited by 51 publications

(64 citation statements)

References 108 publications

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“…The data presented herein substantiate previous findings showing that PRAC plays a role in both T. cruzi development and infectivity and further support its use as a original target for the development of a new chemotherapy against Chagas’ disease [7], [15], [39], [40].…”

Section: Discussionsupporting

confidence: 89%

Combined Approaches for Drug Design Points the Way to Novel Proline Racemase Inhibitor Candidates to Fight Chagas’ Disease

et al. 2013

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Chagas’ disease is caused by Trypanosoma cruzi, a protozoan transmitted to humans by blood-feeding insects, blood transfusion or congenitally. Previous research led us to discover a parasite proline racemase (TcPRAC) and to establish its validity as a target for the design of new chemotherapies against the disease, including its chronic form. A known inhibitor of proline racemases, 2-pyrrolecarboxylic acid (PYC), is water-insoluble. We synthesized soluble pyrazole derivatives, but they proved weak or inactive TcPRAC inhibitors. TcPRAC catalytic site is too small and constrained when bound to PYC to allow efficient search for new inhibitors by virtual screening. Forty-nine intermediate conformations between the opened enzyme structure and the closed liganded one were built by calculating a transition path with a method we developed. A wider range of chemical compounds could dock in the partially opened intermediate active site models in silico. Four models were selected for known substrates and weak inhibitors could dock in them and were used to screen chemical libraries. Two identified soluble compounds, (E)-4-oxopent-2-enoic acid (OxoPA) and its derivative (E)-5-bromo-4-oxopent-2-enoic acid (Br-OxoPA), are irreversible competitive inhibitors that presented stronger activity than PYC on TcPRAC. We show here that increasing doses of OxoPA and Br-OxoPA hamper T. cruzi intracellular differentiation and fate in mammalian host cells. Our data confirm that through to their binding mode, these molecules are interesting and promising as lead compounds for the development of chemotherapies against diseases where active proline racemases play essential roles.

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Section: Discussionsupporting

confidence: 89%

Combined Approaches for Drug Design Points the Way to Novel Proline Racemase Inhibitor Candidates to Fight Chagas’ Disease

et al. 2013

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“…B). As recently proposed (Osorio et al ., ), we divided these virulence factors into 3 groups depending on their predicted function in parasite infectivity ((i) adhesion and invasion, (ii) immune evasion and (iii) resistance to oxidative damage), showing that, for the detected virulence factors, the great majority were extremely down‐regulated in rdEpi (Fig. B).…”

Section: Resultsmentioning

confidence: 99%

Recently differentiated epimastigotes from Trypanosoma cruzi are infective to the mammalian host

Kessler

Contreras

Marliére

et al. 2017

Molecular Microbiology

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Trypanosoma cruzi, the etiologic agent of Chagas disease, has a complex life cycle in which four distinct developmental forms alternate between the insect vector and the mammalian host. It is assumed that replicating epimastigotes present in the insect gut are not infective to mammalian host, a paradigm corroborated by the widely acknowledged fact that only this stage is susceptible to the complement system. In the present work, we establish a T. cruzi in vitro and in vivo epimastigogenesis model to analyze the biological aspects of recently differentiated epimastigotes (rdEpi). We show that both trypomastigote stages of T. cruzi (cell-derived and metacyclic) are able to transform into epimastigotes (processes termed primary and secondary epimastigogenesis, respectively) and that rdEpi have striking properties in comparison to long-term cultured epimastigotes: resistance to complement-mediated lysis and both in vitro (cell culture) and in vivo (mouse) infectivity. Proteomics analysis of all T. cruzi stages reveled a cluster of proteins that were up-regulated only in rdEpi (including ABC transporters and ERO1), suggesting a role for them in rdEpi virulence. The present work introduces a new experimental model for the study of host-parasite interactions, showing that rdEpi can be infective to the mammalian host.

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“…In the generated QPX transcriptome library, seventeen sequences were identified to be involved in antioxidant activity (GO:0016209, Table 1) including catalases (IPR002226), superoxide dismutases (IPR001424, IPR001189), thioredoxin peroxidases (IPR012336, IPR005746), glutathione peroxidases (IPR000889, IPR002109), and ascorbate peroxidases (IPR010255 IPR002207) (Additional file 1). All of these antioxidant molecules have been shown to be effective against endogenous (metabolism related) and exogenous (from host defense) ROS species and are essential for resistance to oxidative stress in many pathogenic protozoans during disease development [56,57]. QPX antioxidant armor suggests that the pathogen is prepared to overcome M. mercenaria hemocyte-derived ROS, and facilitate the establishment of an infection.…”

Section: Resultsmentioning

confidence: 99%

Characterization of the transcriptome and temperature-induced differential gene expression in QPX, the thraustochytrid parasite of hard clams

et al. 2014

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BackgroundThe hard clam or northern quahog, Mercenaria mercenaria, is one of the most valuable seafood products in the United States representing the first marine resource in some Northeastern states. Severe episodes of hard clam mortality have been consistently associated with infections caused by a thraustochytrid parasite called Quahog Parasite Unknown (QPX). QPX is considered as a cold/temperate water organism since the disease occurs only in the coastal waters of the northwestern Atlantic Ocean from Maritime Canada to Virginia. High disease development at cold temperatures was also confirmed in laboratory studies and is thought to be caused predominantly by immunosuppression of the clam host even though the effect of temperature on QPX virulence has not been fully investigated. In this study, the QPX transcriptome was sequenced using Roche 454 technology to better characterize this microbe and initiate research on the molecular basis of QPX virulence towards hard clams.ResultsClose to 18,000 transcriptomic sequences were generated and functionally annotated. Results revealed a wide array of QPX putative virulence factors including a variety of peptidases, antioxidant enzymes, and proteins involved in extracellular mucus production and other secretory proteins potentially involved in interactions with the clam host. Furthermore, a 15 K oligonucleotide array was constructed and used to investigate the effect of temperature on QPX fitness and virulence factors. Results identified a set of QPX molecular chaperones that could explain its adaptation to cold temperatures. Finally, several virulence-related factors were up-regulated at low temperature providing molecular targets for further investigations of increased QPX pathogenicity in cold water conditions.ConclusionsThis is one of the first studies to characterize the transcriptome of a parasitic labyrinthulid, offering new insights into the molecular bases of the pathogenicity of members of this group. Results from the oligoarray study demonstrated the ability of QPX to cope with a wide range of environmental temperatures, including those considered to be suboptimal for clam immunity (low temperature) providing a mechanistic scenario for disease distribution in the field and for high disease prevalence and intensity at low temperature. These results will serve as basis for studies aimed at a better characterization of specific putative virulence factors.

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Virulence factors of Trypanosoma cruzi: who is who?

Cited by 51 publications

References 108 publications

Combined Approaches for Drug Design Points the Way to Novel Proline Racemase Inhibitor Candidates to Fight Chagas’ Disease

Combined Approaches for Drug Design Points the Way to Novel Proline Racemase Inhibitor Candidates to Fight Chagas’ Disease

Recently differentiated epimastigotes from Trypanosoma cruzi are infective to the mammalian host

Characterization of the transcriptome and temperature-induced differential gene expression in QPX, the thraustochytrid parasite of hard clams

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