Fifteen Years after the Definition of DTUs: What Have We Learned?

, the protozoan causative of Chagas disease (ChD), exhibits striking genetic and phenotypic intraspecific diversity, along with ecoepidemiological complexity. Human-pathogen interactions lead to distinct clinical presentations of ChD. In 2009, an international consensus classified strains into six discrete typing units (DTUs), TcI to TcVI, later including TcBat, and proposed reproducible genotyping schemes for DTU identification.

Drug Repurposing in Chagas Disease: Chloroquine Potentiates Benznidazole Activity against Trypanosoma cruzi and .

Drug combinations and drug repurposing have emerged as promising strategies to develop novel treatments for infectious diseases, including Chagas disease. In this study, we aimed to investigate whether the repurposed drugs chloroquine (CQ) and colchicine (COL), known to inhibit Trypanosoma cruzi infection in host cells, could boost the anti-T. cruzi effect of the trypanocidal drug benznidazole (BZN), increasing its therapeutic efficacy while reducing the dose needed to eradicate the parasite.

Pathogen diversity, immunity, and the fate of infections: lessons learned from Trypanosoma cruzi human-host interactions.

The complexity of host-pathogen interactions often leads to distinct clinical outcomes upon infection with different pathogen strains. In this Review, we explore the interactions between the highly diverse Trypanosoma cruzi population and the human host. At least 30% of the 7 million individuals with Chagas disease will develop a severe cardiopathy that is among the deadliest heart diseases known.

Trypanosoma cruzi genetic diversity: impact on transmission cycles and Chagas disease.

Trypanosoma cruzi, the agent of Chagas disease (ChD), exhibits remarkable biological and genetic diversity, along with eco-epidemiological complexity. In order to facilitate communication among researchers aiming at the characterisation of biological and epidemiological aspects of T. cruzi, parasite isolates and strains were partitioned into seven discrete typing units (DTUs), TcI-TcVI and TcBat, identifiable by reproducible genotyping protocols.

Quantification of parasite burden of Trypanosoma cruzi and identification of Discrete Typing Units (DTUs) in blood samples of Latin American immigrants residing in Barcelona, Spain.

Background: Trypanosoma cruzi has a high genetic and biological diversity and has been subdivided into seven genetic lineages, named TcI-TcVI and TcBat. DTUs TcI-TcII-TcV and TcVI are agents of ChD in different regions of Latin America. Due to population movements, the disease is an emergent global public health problem.

Mapping benznidazole resistance in trypanosomatids and exploring evolutionary histories of nitroreductases and ABCG transporter protein sequences.

The nitro-heterocyclic compound benznidazole (BZ) is the first-line drug for the treatment of Chagas disease, caused by the protozoan Trypanosoma cruzi. However, therapeutic failures are common for reasons that include the influences of parasite and host genetics, the effects of toxicity on adherence to treatment, and difficulties in demonstrating parasitological cure. To obtain information on the origin of the resistance to BZ and eliminate from the scenery the participation of the host, initially we mapped the susceptibility to the drug in thirteen species of seven genera of the family Trypanosomatidae.

Investigating the structure-activity relationships of N'-[(5-nitrofuran-2-yl) methylene] substituted hydrazides against Trypanosoma cruzi to design novel active compounds.

Chagas disease, caused by the protozoan Trypanosoma cruzi, is a neglected chronic tropical infection endemic in Latin America. New and effective treatments are urgently needed because the two available drugs - benznidazole (BZD) and nifurtimox (NFX) - have limited curative power in the chronic phase of the disease. We have previously reported the design and synthesis of N'-[(5-nitrofuran-2-yl) methylene] substituted hydrazides that showed high trypanocidal activity against axenic epimastigote forms of three T.

Trypanosoma cruzi genetic diversity: Something new for something known about Chagas disease manifestations, serodiagnosis and drug sensitivity.

The genetic diversity of Trypanosoma cruzi, the protozoan agent of Chagas disease, is widely recognized. At present, T. cruzi is partitioned into seven discrete typing units (DTUs), TcI-TcVI and Tcbat.

A novel ABCG-like transporter of Trypanosoma cruzi is involved in natural resistance to benznidazole.

Benznidazole (BZ) is one of the two drugs used for Chagas disease treatment. Nevertheless therapeutic failures of BZ have been reported, which were mostly attributed to variable drug susceptibility among Trypanosoma cruzi strains. ATP-binding cassette (ABC) transporters are involved in a variety of translocation processes and some members have been implicated in drug resistance.

Designing and exploring active N'-[(5-nitrofuran-2-yl) methylene] substituted hydrazides against three Trypanosoma cruzi strains more prevalent in Chagas disease patients.

Chagas disease affects around 8 million people worldwide and its treatment depends on only two nitroheterocyclic drugs, benznidazole (BZD) and nifurtimox (NFX). Both drugs have limited curative power in chronic phase of disease. Nifuroxazide (NF), a nitroheterocyclic drug, was used as lead to design a set of twenty one compounds in order to improve the anti-Trypanosoma cruzi activity.

ABCG-like transporter of Trypanosoma cruzi involved in benznidazole resistance: gene polymorphisms disclose inter-strain intragenic recombination in hybrid isolates.

Benznidazole (BZ) is one of the two drugs for Chagas disease treatment. In a previous study we showed that the Trypanosoma cruzi ABCG-like transporter gene, named TcABCG1, is over-expressed in parasite strains naturally resistant to BZ and that the gene of TcI BZ-resistant strains exhibited several single nucleotide polymorphisms (SNPs) as compared to the gene of CL Brener BZ-susceptible strain. Here we report the sequence of TcABCG1 gene of fourteen T.

Drug discovery for Chagas disease should consider Trypanosoma cruzi strain diversity.

This opinion piece presents an approach to standardisation of an important aspect of Chagas disease drug discovery and development: selecting Trypanosoma cruzi strains for in vitro screening. We discuss the rationale for strain selection representing T. cruzi diversity and provide recommendations on the preferred parasite stage for drug discovery, T.

Auxin production by the plant trypanosomatid Phytomonas serpens and auxin homoeostasis in infected tomato fruits.

Previously we have characterized the complete gene encoding a pyruvate decarboxylase (PDC)/indolepyruvate decarboxylase (IPDC) of Phytomonas serpens, a trypanosomatid highly abundant in tomato fruits. Phylogenetic analyses indicated that the clade that contains the trypanosomatid protein behaves as a sister group of IPDCs of γ-proteobacteria. Since IPDCs are key enzymes in the biosynthesis of the plant hormone indole-3-acetic acid (IAA), the ability for IAA production by P.

Evidence for T Cell Help in the IgG Response against Tandemly Repetitive Trypanosoma cruzi B13 Protein in Chronic Chagas Disease Patients.

The tandemly repetitive Trypanosoma cruzi B13 protein is an immunodominant antigen among Chagas disease patients. Such repetitive domains may behave as T-independent antigens. However, T cells can recognize B13 epitopes in an HLA class II-restricted fashion and could potentially provide cognate T cell help and boost antibody titers.

Horizontal gene transfer confers fermentative metabolism in the respiratory-deficient plant trypanosomatid Phytomonas serpens.

Among trypanosomatids, the genus Phytomonas is the only one specifically adapted to infect plants. These hosts provide a particular habitat with a plentiful supply of carbohydrates. Phytomonas sp.

The revised Trypanosoma cruzi subspecific nomenclature: rationale, epidemiological relevance and research applications.

The protozoan Trypanosoma cruzi, its mammalian reservoirs, and vectors have existed in nature for millions of years. The human infection, named Chagas disease, is a major public health problem for Latin America. T.

Trypanosoma cruzi benznidazole susceptibility in vitro does not predict the therapeutic outcome of human Chagas disease.

Therapeutic failure of benznidazole (BZ) is widely documented in Chagas disease and has been primarily associated with variations in the drug susceptibility of Trypanosoma cruzi strains. In humans, therapeutic success has been assessed by the negativation of anti-T. cruzi antibodies, a process that may take up to 10 years.

Network genealogy of 195-bp satellite DNA supports the superimposed hybridization hypothesis of Trypanosoma cruzi evolutionary pattern.

Trypanosoma cruzi is highly diverse genetically and has been partitioned into six discrete typing units (DTUs), recently re-named T. cruzi I-VI. Although T.

Mitochondrial bioenergetics and redox state are unaltered in Trypanosoma cruzi isolates with compromised mitochondrial complex I subunit genes.

In trypanosomatids the involvement of mitochondrial complex I in NADH oxidation has long been debated. Here, we took advantage of natural Trypanosoma cruzi mutants which present conspicuous deletions in ND4, ND5 and ND7 genes coding for complex I subunits to further investigate its functionality. Mitochondrial bioenergetics of wild type and complex I mutants showed no significant differences in oxygen consumption or respiratory control ratios in the presence of NADH-linked substrates or FADH(2)-generating succinate.

Trypanosoma cruzi maxicircle heterogeneity in Chagas disease patients from Brazil.

The majority of individuals in the chronic phase of Chagas disease are asymptomatic (indeterminate form, IF). Each year, approximately 3% of them develop lesions in the heart or gastrointestinal tract. Cardiomyopathy (CCHD) is the most severe manifestation of Chagas disease.

Genomic organization and transcription analysis of the 195-bp satellite DNA in Trypanosoma cruzi.

The 195-bp satellite DNA is the most abundant Trypanosoma cruzi repetitive sequence. Here we show by RNA blotting and RT-PCR that 195 SAT is intensely transcribed. We observed a positive correlation between the level of satellite RNA and the abundance of the satellite copies in the genome of T.

Trypanosoma cruzi: involvement of glycoinositolphospholipids in the attachment to the luminal midgut surface of Rhodnius prolixus.

Trypanosoma cruzi epimastigotes adhere in vivo to the luminal surface of their triatomid vector digestive tract by molecular mechanisms, as yet, unknown. Here, we show that the administration of 0.5 microM epimastigote major surface glycoinositolphospholipids (GIPLs) to the infected bloodmeal inhibits up to 90% parasite infection in Rhodnius prolixus.

Trypanosoma cruzi: exploring the nuclear genome of zymodeme 3 stocks by chromosome size polymorphism.

Chagas disease is emerging in the Brazilian Amazon. We evaluated the position of eight zymodeme 3 isolates from Amazonian sylvatic vectors and one human case in relation to Trypanosoma cruzi I and II major groups and hybrid strains by chromosome size polymorphism. Nineteen isolates were analyzed by mapping nine coding sequences on chromosomal bands (0.

Differential transcription profiles in Trypanosoma cruzi associated with clinical forms of Chagas disease: Maxicircle NADH dehydrogenase subunit 7 gene truncation in asymptomatic patient isolates.

The majority of individuals in the chronic phase of Chagas disease are asymptomatic (indeterminate form). Every year 2-3% of these individuals develop severe clinical manifestations (cardiac and digestive forms). In this study a Trypanosoma cruzi DNA microarray was used to compare the transcript profiles of six human isolates: three from asymptomatic and three from cardiac patients.

BayBoots: a model-free Bayesian tool to identify class markers from gene expression data.

One of the goals of gene expression experiments is the identification of differentially expressed genes among populations that could be used as markers. For this purpose, we implemented a model-free Bayesian approach in a user-friendly and freely available web-based tool called BayBoots. In spite of a common misunderstanding that Bayesian and model-free approaches are incompatible, we merged them in the BayBoots implementation using the Kernel density estimator and Rubin 's Bayesian Bootstrap.