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Abstract
The evolution of drug-resistance in pathogens is a major global health threat. Elucidating the molecular basis of pathogen drug-resistance has been the focus of many studies but rarely is it known whether a drug-resistance mechanism identified is universal for the studied pathogen; it has seldom been clarified whether drug-resistance mechanisms vary with the pathogen's genotype. Nevertheless this is of critical importance in gaining an understanding of the complexity of this global threat and in underpinning epidemiological surveillance of pathogen drug resistance in the field. This study aimed to assess the molecular and phenotypic heterogeneity that emerges in natural parasite populations under drug treatment pressure. We studied lines of the protozoan parasite Leishmania (L.) donovani with differential susceptibility to antimonial drugs; the lines being derived from clinical isolates belonging to two distinct genetic populations that circulate in the leishmaniasis endemic region of Nepal. Parasite pathways known to be affected by antimonial drugs were characterised on five experimental levels in the lines of the two populations. Characterisation of DNA sequence, gene expression, protein expression and thiol levels revealed a number of molecular features that mark antimonial-resistant parasites in only one of the two populations studied. A final series of in vitro stress phenotyping experiments confirmed this heterogeneity amongst drug-resistant parasites from the two populations. These data provide evidence that the molecular changes associated with antimonial-resistance in natural Leishmania populations depend on the genetic background of the Leishmania population, which has resulted in a divergent set of resistance markers in the Leishmania populations. This heterogeneity of parasite adaptations provides severe challenges for the control of drug resistance in the field and the design of molecular surveillance tools for widespread applicability.
Highlights
Leishmania, a protozoan parasite transmitted by phlebotomine sand flies, causes a neglected infectious disease commonly referred to as leishmaniasis
The mechanisms developed by pathogens to become resistant against existing drug treatments have been studied for many years but these studies have frequently scrutinized a few lines of the pathogen and rarely is it known whether the mechanisms identified occur in all pathogen populations present in endemic regions
In this study we assessed the diversity amongst drug-resistant parasites which emerged under treatment pressure in a natural parasite population
Summary
Leishmania, a protozoan parasite transmitted by phlebotomine sand flies, causes a neglected infectious disease commonly referred to as leishmaniasis. The species Leishmania (Leishmania) donovani is the causative agent of visceral leishmaniasis (VL) or kala-azar, the most severe form of leishmaniasis which is lethal if left untreated [1,2]. Pentavalent antimonials, such as sodium stibogluconate (SSG), have been the first-line treatment for leishmaniasis worldwide for more than 70 years. This therapy is challenged by emergence of resistant parasites [3,4,5,6], a phenomenon best documented in the Indian subcontinent with SSGresistant L. In the neighbouring Nepalese VL endemic region VL patients infected with SSG-resistant parasites were found to have only a 25% risk of SSG treatment failure [8]
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