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ASSESSMENT OF DRUG RESISTANCE RELATED GENES AS CANDIDATE MARKERS FOR TREATMENT OUTCOME PREDICTION OF CUTANEOUS LEISHMANIASIS IN BRAZIL
Treatment failure
Molecular markers
Leishmania braziliensis
Leishmania guyanensis
Author
Affilliation
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa em Leishmaniose/Coleção de Leishmania. Laboratório de Biologia Computacional e Sistemas. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto de Pesquisa Clínica Evandro Chagas. Laboratório de Pesquisa em Farmacogenética. Rio de Janeiro, RJ, Brasil,
Universidade de Brasília. Núcleo de Medicina Tropical. Laboratório de Leishmanioses. Brasília, DF, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Computacional e Sistemas. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa em Leishmaniose/Coleção de Leishmania. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto de Pesquisa Clínica Evandro Chagas. Laboratório de Pesquisa em Farmacogenética. Rio de Janeiro, RJ, Brasil,
Universidade de Brasília. Núcleo de Medicina Tropical. Laboratório de Leishmanioses. Brasília, DF, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Computacional e Sistemas. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa em Leishmaniose/Coleção de Leishmania. Rio de Janeiro, RJ, Brasil.
Abstract
The great public health problem posed by leishmaniasis has substantially worsened in recent years by the emergence of clinical failure. In Brazil, the poor prognosis observed for patients infected by Leishmania braziliensis (Lb) or L. guyanensis (Lg) may be related to parasite drug resistance. In the present study, 19 Lb and 29 Lg isolates were obtained from infected patients with different treatment outcomes. Translated amino acid sequence polymorphisms from four described antimony resistance related genes
(AQP1, hsp70, MRPA and TRYR) were tested as candidate markers for antimonial treatment failure prediction. Possibly due to the low intraspecific variability observed in Lg samples, none of the prediction models had good prognosis values. Most strikingly, one mutation (T579A) found in hsp70 of Lb samples could predict 75% of the antimonial treatment failure clinical cases. Moreover, a multiple logistic regression model showed that the change from adenine to guanine at position 1735 of the hsp70 gene, which is responsible for the T579A mutation, significantly increased the chance of Lb clinical isolates to be associated with treatment failure (OR = 7.29; CI 95% = [1.17, 45.25]; p = 0.0331). The use of molecular markers to predict treatment outcome presents practical and economic advantages as it allows the development of rapid assays to monitor the emergence of drug resistant parasites that can be clinically applied to aid the prognosis of cutaneous leishmaniasis in Brazil.
Keywords
Cutaneous leishmaniasisTreatment failure
Molecular markers
Leishmania braziliensis
Leishmania guyanensis
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