Trypanosoma cruzi: Characterisation of the gene encoding tyrosine aminotransferase in benznidazole-resistant and susceptible populations

Rêgo, Juciane Vaz; Murta, Silvane Maria Fonseca; Nirdé, Philippe; Nogueira, Fernanda B.; Andrade, Hélida Monteiro de; Romanha, Álvaro J.

doi:10.1016/j.exppara.2007.05.013

Cited by 12 publications

(6 citation statements)

References 33 publications

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“…66 Many molecular studies have compared those two populations to identify resistance markers. [67][68][69] Although no correlation was detected, other studies have found differences in the in vitroinduced BZ-resistant strains (17WTS X 17LER). 67 More recently, a proteomic analysis of BZS-Y/BZR-Y and 17WTS/ 17LER also identified many overexpressed proteins in the BZR-Y population.…”

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confidence: 54%

Intraspecies Variation in Trypanosoma cruzi GPI-Mucins: Biological Activities and Differential Expression of α-Galactosyl Residues

Soares¹,

Torrecilhas²,

Assis³

et al. 2012

The American Society of Tropical Medicine and Hygiene

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confidence: 54%

Intraspecies Variation in Trypanosoma cruzi GPI-Mucins: Biological Activities and Differential Expression of α-Galactosyl Residues

Soares¹,

Torrecilhas²,

Assis³

et al. 2012

The American Society of Tropical Medicine and Hygiene

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“…Previous data obtained by our group, also describes differences between mRNA and protein levels of some T. cruzi genes . Although the levels of TcTAT (tyrosine aminotransferase) and TcHSP-70 (heat shock protein 70 kDa) mRNAs were higher in the T. cruzi BZ-resistant population 17LER, no corresponding increases were observed in the levels of TcTAT and TcHSP-70 protein expression [11,44]. …”

Section: Discussionmentioning

confidence: 99%

Molecular characterization of the hexose transporter gene in benznidazole resistant and susceptible populations of Trypanosoma cruzi

et al. 2012

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BackgroundHexose transporters (HT) are membrane proteins involved in the uptake of energy-supplying glucose and other hexoses into the cell. Previous studies employing the Differential Display technique have shown that the transcription level of the HT gene from T. cruzi (TcrHT) is higher in an in vitro-induced benznidazole (BZ)-resistant population of the parasite (17 LER) than in its susceptible counterpart (17 WTS).MethodsIn the present study, TcrHT has been characterized in populations and strains of T. cruzi that are resistant or susceptible to BZ. We investigated the copy number and chromosomal location of the gene, the levels of TcrHT mRNA and of TcrHT activity, and the phylogenetic relationship between TcrHT and HTs from other organisms.ResultsIn silico analyses revealed that 15 sequences of the TcrHT gene are present in the T. cruzi genome, considering both CL Brener haplotypes. Southern blot analyses confirmed that the gene is present as a multicopy tandem array and indicated a nucleotide sequence polymorphism associated to T. cruzi group I or II. Karyotype analyses revealed that TcrHT is located in two chromosomal bands varying in size from 1.85 to 2.6 Mb depending on the strain of T. cruzi. The sequence of amino acids in the HT from T. cruzi is closely related to the HT sequences of Leishmania species according to phylogenetic analysis. Northern blot and quantitative real-time reverse transcriptase polymerase chain reaction analyses revealed that TcrHT transcripts are 2.6-fold higher in the resistant 17 LER population than in the susceptible 17 WTS. Interestingly, the hexose transporter activity was 40% lower in the 17 LER population than in all other T. cruzi samples analyzed. This phenotype was detected only in the in vitro-induced BZ resistant population, but not in the in vivo-selected or naturally BZ resistant T. cruzi samples. Sequencing analysis revealed that the amino acid sequences of the TcrHT from 17WTS and 17LER populations are identical. This result suggests that the difference in glucose transport between 17WTS and 17LER populations is not due to point mutations, but probably due to lower protein expression level.ConclusionThe BZ resistant population 17 LER presents a decrease in glucose uptake in response to drug pressure.

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“…Until recently though, the molecular basis for resistance had not been elucidated and appeared complex. Parasites selected for nitroheterocyclic drug resistance often displayed significant karyotypic alterations (Refs 120, 121), with the resulting effects on global gene expression masking the precise mechanism(s) (Refs 123, 124, 125, 126, 127, 128, 129). A link between the activity of a trypanosome type I NTR and cross-resistance to nifurtimox and benznidazole has now been established in T. cruzi and T. brucei .…”

Section: Chagas Diseasementioning

confidence: 99%

Trypanocidal drugs: mechanisms, resistance and new targets

Wilkinson

Kelly

2009

Expert Rev. Mol. Med.

213

183

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The protozoan parasites Trypanosoma brucei and Trypanosoma cruzi are the causative agents of African trypanosomiasis and Chagas disease, respectively. These are debilitating infections that exert a considerable health burden on some of the poorest people on the planet. Treatment of trypanosome infections is dependent on a small number of drugs that have limited efficacy and can cause severe side effects. Here, we review the properties of these drugs and describe new findings on their modes of action and the mechanisms by which resistance can arise. We further outline how a greater understanding of parasite biology is being exploited in the search for novel chemotherapeutic agents. This effort is being facilitated by new research networks that involve academic and biotechnology/pharmaceutical organisations, supported by public-private partnerships, and are bringing a new dynamism and purpose to the search for trypanocidal agents.

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Trypanosoma cruzi: Characterisation of the gene encoding tyrosine aminotransferase in benznidazole-resistant and susceptible populations

Cited by 12 publications

References 33 publications

Intraspecies Variation in Trypanosoma cruzi GPI-Mucins: Biological Activities and Differential Expression of α-Galactosyl Residues

Intraspecies Variation in Trypanosoma cruzi GPI-Mucins: Biological Activities and Differential Expression of α-Galactosyl Residues

Molecular characterization of the hexose transporter gene in benznidazole resistant and susceptible populations of Trypanosoma cruzi

Trypanocidal drugs: mechanisms, resistance and new targets

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