A Leishmania infantum genetic marker associated with miltefosine treatment failure for visceral leishmaniasisResearch in context
Juliana B.T. Carnielli,
Kathryn Crouch,
Sarah Forrester,
Vladimir Costa Silva,
Sílvio F.G. Carvalho,
Jeziel D. Damasceno,
Elaine Brown,
Nicholas J. Dickens,
Dorcas L. Costa,
Carlos H.N. Costa,
Reynaldo Dietze,
Daniel C. Jeffares,
Jeremy C. Mottram
Affiliations
Juliana B.T. Carnielli
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.; Correspondence to: J. B. T. Carnielli, Centre for Immunology and Infection, Department of Biology, University of York, Wentworth Way, Heslington, York YO10 5DD, United Kingdom.
Kathryn Crouch
Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, United Kingdom.
Sarah Forrester
Centre for Immunology and Infection, Department of Biology, University of York, United Kingdom.
Vladimir Costa Silva
Laboratório de Pesquisas em Leishmanioses, Instituto de Doenças Tropicais Natan Portella, Universidade Federal do Piauí, Teresina, PI, Brazil.
Sílvio F.G. Carvalho
Hospital Universitário Clemente de Faria, Universidade Estadual de Montes Claros, Montes Claros, MG, Brazil.
Jeziel D. Damasceno
Laboratório de Biologia Molecular de Leishmania, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
Elaine Brown
Centre for Immunology and Infection, Department of Biology, University of York, United Kingdom.
Nicholas J. Dickens
Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, United Kingdom.
Dorcas L. Costa
Laboratório de Pesquisas em Leishmanioses, Instituto de Doenças Tropicais Natan Portella, Universidade Federal do Piauí, Teresina, PI, Brazil.
Carlos H.N. Costa
Laboratório de Pesquisas em Leishmanioses, Instituto de Doenças Tropicais Natan Portella, Universidade Federal do Piauí, Teresina, PI, Brazil.
Reynaldo Dietze
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.
Daniel C. Jeffares
Centre for Immunology and Infection, Department of Biology, University of York, United Kingdom.
Jeremy C. Mottram
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.; Correspondence to: J. C. Mottram, Centre for Immunology and Infection, Department of Biology, University of York, Wentworth Way, Heslington, York YO10 5DD, United Kingdom.
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 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. Keywords: Visceral leishmaniasis, Miltefosine treatment failure, Whole-genome sequencing, Miltefosine Susceptibility Locus, Prognostic marker
