Impact of Dual Infections on Chemotherapeutic Efficacy in BALB/c Mice Infected with Major Genotypes ofTrypanosoma cruzi

Abstract

The aim of this work was to investigate the impact of dual infections with stocks of Trypanosoma cruzi major genotypes on benznidazole (BZ) treatment efficacy. For this purpose, T. cruzi stocks representative of the genetic T. cruzi lineages, displaying different susceptibilities to BZ, belonging to the major T. cruzi genotypes broadly dispersed in North and South America and important in Chagas' disease epidemiology were used. Therapeutic efficacy was observed in 27.8% of the animals treated. Following BZ susceptibility classification, significant differences were observed in dual infections on the major genotype level, demonstrating that combinations of genotypes 19؉39 and genotypes 19؉32 led to a shift in the expected BZ susceptibility profile toward the resistance pattern. Analysis on the T. cruzi stock level demonstrated that 9 out of 24 dual infections shifted the expected BZ susceptibility profile compared with the respective single infections, including shifts toward lower and higher BZ susceptibilities. Microsatellite identification was able to identify a mixture of T. cruzi stocks in 7.7% of the T. cruzi isolates from infected and untreated mice (6.9%) and infected and treated but not cured mice (9.0%), revealing in some mixtures of BZ-susceptible and -resistant stocks that the T. cruzi stock identified after BZ treatment was previously susceptible in single infections. Considering the clonal structure and evolution of T. cruzi, an unexpected result was the identification of parasite subpopulations with distinct microsatellite alleles in relation to the original stocks observed in 12.2% of the isolates. Taken together, the data suggest that mixed infections, already verified in nature, may have an important impact on the efficacy of chemotherapy.

Usefulness of PCR-based assays to assess drug efficacy in Chagas disease chemotherapy: value and limitations

“…Mixed infections show responses to benznidazole treatment distinct from the expected response based on single-infection analyses (Martins et al 2007), suggesting that the expected correlation between susceptibility to treatment is difficult to establish for dual infections when genetic combination occurs.…”

Genotyping of Trypanosoma cruzi Sublineage in Human Samples from a North-East Argentina Area by Hybridization with DNA Probes and Specific Polymerase Chain Reaction (PCR)

“…[5][6][7][8] Furthermore, different T. cruzi genotypes have been correlated with different virulence and antibiotic resistance. [9][10][11][12][13] These findings indicate that the genotype identification may be relevant to provide a prognosis of disease progression and/or differential treatment decisions based on the infective strain.…”

Effects of artesunate against Trypanosma cruzi

“…Thus, there is an imperative need for improved, easy to manage and less toxic anti-T. cruzi drugs that are inexpensive, and which can also be administered during pregnancy. In studies of drug susceptibility, a wide range of responses to trypanocidal drugs were documented for T. cruzi isolates circulating in different regions of Latin America (Andrade et al, 1985;Martins et al, 2007;Toledo et al, 2003). Herein, we investigated the in vitro action of AS against of T. cruzi strains originated in different endemic regions of Chagas disease and found that it is an effective compound in terms of inhibiting epimastigote and amastigote growth at low micromolar concentrations.…”