Assessment of drug resistance related genes as candidate markers for treatment outcome prediction of cutaneous leishmaniasis in Brazil

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.

Dendritic Cells andLeishmaniaInfection: Adding Layers of Complexity to a Complex Disease

“…This approach raised new insights into how effector mechanisms may be regulated within the granuloma and revealed a useful tool to interpret how interventions may operate. For cutaneous leishmaniasis, the analysis of DNA sequence of L. braziliensis and L. guyanensis isolated from patients with different treatment outcomes identified polymorphisms related to drug resistance [ 92 ]. This study showed that genes related to drug resistance could be used to discriminate the two species of the subgenus L. Viannia and also could predict treatment failure.…”

Favorable responses to treatment with 5 mg Sbv/kg/day meglumine antimoniate in patients with American tegumentary leishmaniasis acquired in different Brazilian regions

“…Results from our study and other studies 30,34,35 indicate that the L. (V.) braziliensis population endemic to the state of Rio de Janeiro presents a homogeneous genetic pattern with low variability, which could explain the favorable therapeutic response to MA observed in patients who were infected in this state. However, therapeutic response to antimonial drugs may vary in states other than Rio de Janeiro, where ATL may be caused by different Leishmania species or by an L. (V.) braziliensis subpopulation with a high genetic variability 6,8,50 . Despite this fact, the results of the current study confirmed the findings of previous studies performed at INI/Fiocruz that included patients from other Brazilian states, 10,20,23,33 and suggest that patients infected by L. (V.) braziliensis or other Leishmania species may respond to low-dose MA, regardless of their geographic origin in Brazil.…”

Intrachromosomal Amplification, Locus Deletion and Point Mutation in the Aquaglyceroporin AQP1 Gene in Antimony Resistant Leishmania (Viannia) guyanensis

“…The L . guyanensis AQP1 sequence GU368155.1 (strain MHOM/BR/1997/NMT-MAO 328P clone B) was used as an additional reference [ 81 ]. Alignment was performed with ClustalW2 and plotted using TEXshade [ 79 , 80 ].…”