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

Author(s)

Franco, Jaques ^[1] ; Ferreira, Renata C. ^[2] ; Ienne, Susan ^[1] ; Zingales, Bianca ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Quim, Dept Bioquim, BR-05508000 Sao Paulo, SP - Brazil

^[2] Univ Fed Sao Paulo, Lab Genom Evolut & Biocomplexidade, BR-04039032 Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: INFECTION GENETICS AND EVOLUTION; v. 31, p. 198-208, APR 2015.
• Web of Science Citations: 11

Abstract

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 Trypanosoma cruzi strains, with diverse degrees of BZ sensitivity and belonging to different discrete typing units (DTUs) and Tcbat group. Although DTU-specific SNPs and amino acid changes were identified, no direct correlation with BZ-resistance phenotype was found. Thus, it is plausible that the transporter abundance is a determinant factor for drug resistance, as pointed out above. Sequence data were used for Bayesian phylogenies and network genealogy analysis. The network showed a high degree of reticulation suggesting genetic exchange between the parasites. TcI and TcII clades were clearly separated. Tcbat sequences were close to TcI. A fourth clade clustered TcABCG1 haplotypes of TcV, TcVI and TcIII strains, with closer proximity to TcI. Analysis of the recombination patterns indicated that hybrid strains contain haplotypes that are mosaics most likely derived by intragenic recombination of parental sequences. The data confirm that TcII and Mill as the parentals of TcV and TcVI DTUs. Since genetic fingerprint of TcI was found in TcIII, we sustain the previously proposed ``Two Hybridization model{''} for the origin of hybrid strains. Among the twenty best BLASTP hits in databases, orthologues of TcABCG1 transporter were found in Leishmania spp. and African trypanosomes, though their function remains undescribed. (C) 2015 Elsevier B.V. All rights reserved. (AU)

• FAPESP's process: 13/13333-8 - Chemotherapy for Chagas Disease: therapeutic failures to benznidazole and screening of candidates for treatment alternatives
• Grantee: Bianca Silvana Zingales
• Support type: Regular Research Grants
• FAPESP's process: 09/01230-4 - Clinical aplications on the molecular systematic of Candida spp. in the perspective of comparative genomics of gene genealogies and Bayesian analyses
• Grantee: Renata Carmona e Ferreira
• Support type: Scholarships in Brazil - Post-Doctorate