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

Author(s):Show less -

Carnielli, Juliana B. T. ^{[1, 2, 3]} ; Crouch, Kathryn ^[1] ; Forrester, Sarah ^[2] ; Silva, Vladimir Costa ^[4] ; Carvalho, Silvio F. G. ^[5] ; Damasceno, Jeziel D. ^[6] ; Brown, Elaine ^[2] ; Dickens, Nicholas J. ^[1] ; Costa, Dorcas L. ^[4] ; Costa, Carlos H. N. ^[4] ; Dietze, Reynaldo ^{[3, 7]} ; Jeffares, Daniel C. ^[2] ; Mottram, Jeremy C. ^{[1, 2]}

Affiliation

^[1] Univ Glasgow, Inst Infect Immun & Inflammat, Wellcome Ctr Mol Parasitol, Glasgow, Lanark - Scotland

^[2] Univ York, Dept Biol, Ctr Immunol & Infect, Wentworth Way, York YO10 5DD, N Yorkshire - England

^[3] Univ Fed Espirito Santo, Nucleo Doencas Infecciosas, Lab Leishmanioses, Vitoria, ES - Brazil

^[4] Univ Fed Piaui, Inst Doencas Tropicais Natan Portella, Lab Pesquisas Leishmanioses, Teresina, PI - Brazil

^[5] Univ Estadual Montes Claros, Hosp Univ Clemente Faria, Montes Claros, MG - Brazil

^[6] Univ Sao Paulo, Fac Med Ribeirao Preto, Lab Biol Mol Leishmania, Ribeirao Preto, SP - Brazil

^[7] Univ NOVA Lisboa, Inst Higiene & Med Trop, Lisbon - Portugal

• Document type: Journal article
• Source: EBIOMEDICINE; v. 36, p. 83-91, OCT 2018.
• Web of Science Citations: 8

Abstract

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. infantum Miltefosine 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 dine 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. (C) 2018 The Authors. Published by Elsevier B.V. (AU)

• FAPESP's process: 14/00751-9 - Identification of LmRad9, LmHus1 and LmRad1-interacting proteins and generation of a LmHus1 conditional knockout cell line
• Grantee: Jeziel Dener Damasceno
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor