Trypanosoma cruzi: ancestral genomes and population structure

Pena, Sérgio D.J.; Machado, Carlos Renato; Macedo, Andréa Mara

doi:10.1590/s0074-02762009000900016

Cited by 23 publications

(14 citation statements)

References 43 publications

(53 reference statements)

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“…Here we have documented the high trypanocidal activity of DB766, regardless of the drug resistance profile. The significant activity of DB766 upon several parasite strains represents a very important finding, since T. cruzi comprises numerous clonal populations with distinct characteristics, such as different sensitivity to Nf and Bz, diverse biological parameters, and enzymatic diversity (26,28,43,(47)(48)(49). In addition, strain heterogeneity may also be related to the different clinical manifestations and outcomes in CD (3,38).…”

Section: Discussionmentioning

confidence: 99%

Arylimidamide DB766, a Potential Chemotherapeutic Candidate for Chagas' Disease Treatment

Batista

Oliveira

et al. 2010

Antimicrob Agents Chemother

190

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Chagas' disease, a neglected tropical illness for which current therapy is unsatisfactory, is caused by the intracellular parasite Trypanosoma cruzi. The goal of this work is to investigate the in vitro and in vivo effects of the arylimidamide (AIA) DB766 against T. cruzi. This arylimidamide exhibits strong trypanocidal activity and excellent selectivity for bloodstream trypomastigotes and intracellular amastigotes (Y strain), giving IC 50 s (drug concentrations that reduce 50% of the number of the treated parasites) of 60 and 25 nM, respectively. DB766 also exerts striking effects upon different parasite stocks, including those naturally resistant to benznidazole, and displays higher activity in vitro than the reference drugs. By fluorescent and transmission electron microscopy analyses, we found that this AIA localizes in DNA-enriched compartments and induces considerable damage to the mitochondria. DB766 effectively reduces the parasite load in the blood and cardiac tissue and presents efficacy similar to that of benznidazole in mouse models of T. cruzi infection employing the Y and Colombian strains, using oral and intraperitoneal doses of up to 100 mg/kg/day that were given after the establishment of parasite infection. This AIA ameliorates electrocardiographic alterations, reduces hepatic and heart lesions induced by the infection, and provides 90 to 100% protection against mortality, which is similar to that provided by benznidazole. Our data clearly show the trypanocidal efficacy of DB766, suggesting that this AIA may represent a new lead compound candidate to Chagas' disease treatment.

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Section: Discussionmentioning

confidence: 99%

Arylimidamide DB766, a Potential Chemotherapeutic Candidate for Chagas' Disease Treatment

Batista

Oliveira

et al. 2010

Antimicrob Agents Chemother

190

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“…Ultrastructural studies on the developmental forms of T. cruzi are performed largely with epimastigotes, which grow luxuriously in vitro, the closest approximation of the parasite found in the gut of the invertebrate host (312). A detailed description of the structures and functions can be found in specialized texts (103,437,438).…”

Section: Ultrastructure Genome Organization and Function Of Trypanomentioning

confidence: 99%

Pathogenesis of Chagas' Disease: Parasite Persistence and Autoimmunity

et al. 2011

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SUMMARY Acute Trypanosoma cruzi infections can be asymptomatic, but chronically infected individuals can die of Chagas' disease. The transfer of the parasite mitochondrial kinetoplast DNA (kDNA) minicircle to the genome of chagasic patients can explain the pathogenesis of the disease; in cases of Chagas' disease with evident cardiomyopathy, the kDNA minicircles integrate mainly into retrotransposons at several chromosomes, but the minicircles are also detected in coding regions of genes that regulate cell growth, differentiation, and immune responses. An accurate evaluation of the role played by the genotype alterations in the autoimmune rejection of self-tissues in Chagas' disease is achieved with the cross-kingdom chicken model system, which is refractory to T. cruzi infections. The inoculation of T. cruzi into embryonated eggs prior to incubation generates parasite-free chicks, which retain the kDNA minicircle sequence mainly in the macrochromosome coding genes. Crossbreeding transfers the kDNA mutations to the chicken progeny. The kDNA-mutated chickens develop severe cardiomyopathy in adult life and die of heart failure. The phenotyping of the lesions revealed that cytotoxic CD45, CD8 + γδ, and CD8α + T lymphocytes carry out the rejection of the chicken heart. These results suggest that the inflammatory cardiomyopathy of Chagas' disease is a genetically driven autoimmune disease.

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“…Moreover, strains of T . cruzi showed distinct biological characteristics like infectivity, genetic and protein polymorphism (Buscaglia and Di Noia 2003 ;Pena et al 2009 ;Yoshida 2009 ;Ramirez et al 2010 ;Telleria et al 2010 ;Lima et al 2012 ). The high heterogeneity amongst the strains leads to distinct initiatives for their classifi cation.…”

Section: Introduction: General Considerations On the Variability Of Tmentioning

confidence: 99%

The Gp85 Surface Glycoproteins from Trypanosoma cruzi

Mattos

Tonelli

Colli

et al. 2013

Subcellular Biochemistry

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Trypanosoma cruzi strains show distinctive characteristics as genetic polymorphism and infectivity. Large repertoires of molecules, such as the Gp85 glycoproteins, members of the Gp85/Trans-sialidase superfamily, as well as multiple signaling pathways, are associated with invasion of mammalian cells by the parasite. Due to the large number of expressed members, encoded by more than 700 genes, the research focused on this superfamily conserved sequences is discussed. Binding sites to laminin have been identified at the N-terminus of the Gp85 molecules. Interestingly, the T. cruzi protein phosphorylation profile is changed upon parasite binding to laminin (or fibronectin), particularly the cytoskeletal proteins such as those from the paraflagellar rod and the tubulins, which are both markedly dephosphorylated. Detailed analysis of the signaling cascades triggered upon T. cruzi binding to extracellular matrix (ECM) proteins revealed the involvement of the MAPK/ERK pathway in this event. At the C-terminus, the conserved FLY sequence is a cytokeratin-binding domain and is involved in augmented host cell invasion in vitro and high levels of parasitemia in vivo. FLY, which is associated to tissue tropism and preferentially binds to the heart vasculature may somehow be correlated with the severe cardiac form, an important clinical manifestation of chronic Chagas' disease.

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Trypanosoma cruzi: ancestral genomes and population structure

Abstract: Although the genome of Trypanosoma cruzi has been completely sequenced, little is known about its population structure and evolution. Since 1999, two

Cited by 23 publications

References 43 publications

Arylimidamide DB766, a Potential Chemotherapeutic Candidate for Chagas' Disease Treatment

Arylimidamide DB766, a Potential Chemotherapeutic Candidate for Chagas' Disease Treatment

Pathogenesis of Chagas' Disease: Parasite Persistence and Autoimmunity

The Gp85 Surface Glycoproteins from Trypanosoma cruzi

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