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

Autor:	Carnielli JBT; Laboratório de Leishmanioses, Núcleo de Doenças Infecciosas, Universidade Federal do Espírito Santo, Vitória, ES, Brazil.; Centre for Immunology and Infection, Department of Biology, University of York, United Kingdom.; Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, United Kingdom.. Electronic address: juliana.carnielli@york.ac.uk., Crouch K; Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, United Kingdom., Forrester S; Centre for Immunology and Infection, Department of Biology, University of York, United Kingdom., Silva VC; Laboratório de Pesquisas em Leishmanioses, Instituto de Doenças Tropicais Natan Portella, Universidade Federal do Piauí, Teresina, PI, Brazil., Carvalho SFG; Hospital Universitário Clemente de Faria, Universidade Estadual de Montes Claros, Montes Claros, MG, Brazil., Damasceno JD; Laboratório de Biologia Molecular de Leishmania, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil., Brown E; Centre for Immunology and Infection, Department of Biology, University of York, United Kingdom., Dickens NJ; Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, United Kingdom., Costa DL; Laboratório de Pesquisas em Leishmanioses, Instituto de Doenças Tropicais Natan Portella, Universidade Federal do Piauí, Teresina, PI, Brazil., Costa CHN; Laboratório de Pesquisas em Leishmanioses, Instituto de Doenças Tropicais Natan Portella, Universidade Federal do Piauí, Teresina, PI, Brazil., Dietze R; Laboratório de Leishmanioses, Núcleo de Doenças Infecciosas, Universidade Federal do Espírito Santo, Vitória, ES, Brazil.; Instituto de Higiene e Medicina Tropical, Universidade NOVA de Lisboa, Lisbon, Portugal., Jeffares DC; Centre for Immunology and Infection, Department of Biology, University of York, United Kingdom., Mottram JC; Centre for Immunology and Infection, Department of Biology, University of York, United Kingdom.; Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, United Kingdom.. Electronic address: jeremy.mottram@york.ac.uk.
Jazyk:	angličtina
Zdroj:	EBioMedicine [EBioMedicine] 2018 Oct; Vol. 36, pp. 83-91. Date of Electronic Publication: 2018 Sep 27.
DOI:	10.1016/j.ebiom.2018.09.029
Abstrakt:	Background: Miltefosine has been used successfully to treat visceral leishmaniasis (VL) in India, but it was unsuccessful for VL in a clinical trial in Brazil. Methods: To 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. Findings: A 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%. Interpretation: Knowledge 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. FUND: CNPq, FAPES, GCRF MRC and Wellcome Trust. (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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