A Leishmania infantum genetic marker associated with miltefosine treatment failure for visceral leishmaniasis

Abstract

BackgroundMiltefosine has been used successfully to treat visceral leishmaniasis (VL) in India, but it was unsuccessful for VL in a clinical trial in Brazil.MethodsTo identify molecular markers that predict VL treatment failure whole genome sequencing of 26 L. infantum isolates, from cured and relapsed patients allowed a GWAS analysis of SNPs, gene and chromosome copy number variations.FindingsA strong association was identified (p = 0·0005) between the presence of a genetically stable L. infantumMiltefosine Sensitivity Locus (MSL), and a positive response to miltefosine treatment. The risk of treatment failure increased 9·4-fold (95% CI 2·11–53·54) when an isolate did not have the MSL. The complete absence of the MSL predicted miltefosine failure with 0·92 (95% CI 0·65–0·996) sensitivity and 0·78 (95% CI 0·52–0·92) specificity. A genotyping survey of L. infantum (n = 157) showed that the frequency of MSL varies in a cline from 95% in North East Brazil to <5% in the South East. The MSL was found in the genomes of all L. infantum and L. donovani sequenced isolates from the Old World (n = 671), where miltefosine can have a cure rate higher than 93%.InterpretationKnowledge on the presence or absence of the MSL in L. infantum will allow stratification of patients prior to treatment, helping to establish better therapeutic strategies for VL treatment.FundCNPq, FAPES, GCRF MRC and Wellcome Trust.

Trans-Atlantic Spill Over: Deconstructing the Ecological Adaptation of Leishmania Infantum in the Americas

“…In that circumstance, such signal could eventually be associated with phenotypes or ecological traits. This latter possibility is supported by recent work from Carnielli et al, [60]. The authors described a full deletion comprising four genes in tandem on chromosome 31 (the only stable chromosome within the aneuploid mosaicism) of Brazilian L. infantum strains.…”

“…This pattern indicates fitness gain in response to Brazilian ecological conditions, although more consistent screening of NW and WO strains must be done to better determining frequency and geographic distribution of deleted and non-deleted samples (Figure 1). The mechanism of loss of the genomic region is possibly mediated by homologous recombination between repetitive elements bordering the locus [60]. Thus, existence of deleted sub-population among non-deleted Leishmania cells cannot be discarded -especially in OW strains, a hypothesis yet to be tested.…”

“…The possibility of extinction, or reduced frequency of deletion parasites in the OW as a result of changes in environments and socioeconomic patterns [64] cannot be disregarded. It is also important to consider the possibility of recombination between the Del and NonDel genotypes, since both were detected cocirculating, and even corresponding to subpopulation within the same isolate [60].…”

Trans-Atlantic Spillover: Deconstructing the Ecological Adaptation of Leishmania infantum in the Americas

“…In that circumstance, such signals could eventually be associated with phenotypes or ecological traits. This latter possibility is supported by recent work from Carnielli et al [61]. The authors described a full deletion comprising four genes in tandem on chromosome 31 (the only stable chromosome within the aneuploid mosaicism) of Brazilian L. infantum strains.…”

“…This pattern indicates fitness gain in response to Brazilian ecological conditions, although more consistent screening of NW and OW strains must be done to better determine frequency and geographic distribution of deleted (Del) and non-deleted (NonDel) samples (Figure 1). The mechanism of loss of the genomic region is possibly mediated by homologous recombination between repetitive elements bordering the locus [61]. Thus, the existence of deleted sub-population among non-deleted Leishmania cells cannot be discarded-especially in OW strains, a hypothesis yet to be tested.…”