Whole genome sequencing distinguishes between relapse and reinfection in recurrent leprosy cases.
- Stefani MMA Tropical Pathology and Public Health Institute, Federal University of Goiás, Goiania, Goiás, Brazil.
- Avanzi C Global Health Institute, École Polytechnique Fédérale de Lausanne, Switzerland.
- Bührer-Sékula S Tropical Pathology and Public Health Institute, Federal University of Goiás, Goiania, Goiás, Brazil.
- Benjak A Global Health Institute, École Polytechnique Fédérale de Lausanne, Switzerland.
- Loiseau C Global Health Institute, École Polytechnique Fédérale de Lausanne, Switzerland.
- Singh P Global Health Institute, École Polytechnique Fédérale de Lausanne, Switzerland.
- Pontes MAA Dona Libânia Dermatology Centre, Fortaleza, Ceará, Brazil.
- Gonçalves HS Dona Libânia Dermatology Centre, Fortaleza, Ceará, Brazil.
- Hungria EM Tropical Pathology and Public Health Institute, Federal University of Goiás, Goiania, Goiás, Brazil.
- Busso P Global Health Institute, École Polytechnique Fédérale de Lausanne, Switzerland.
- Piton J Global Health Institute, École Polytechnique Fédérale de Lausanne, Switzerland.
- Silveira MIS Dona Libânia Dermatology Centre, Fortaleza, Ceará, Brazil.
- Cruz R University of Amazonas State, Manaus, Amazonas, Brazil.
- Schetinni A Tropical Dermatology and Venerology, Alfredo da Matta Foundation, Manaus, Amazonas, Brazil.
- Costa MB Faculty of Medicine, Federal University of Goiás, Goiania, Goiás, Brazil.
- Virmond MCL Lauro Souza Lima Institute, Bauru, São Paulo, Brazil.
- Diorio SM Lauro Souza Lima Institute, Bauru, São Paulo, Brazil.
- Dias-Baptista IMF Lauro Souza Lima Institute, Bauru, São Paulo, Brazil.
- Rosa PS Lauro Souza Lima Institute, Bauru, São Paulo, Brazil.
- Matsuoka M Department of Mycobacteriology, Leprosy Research Center, National Institute of Infectious Diseases, Higashimurayama, Tokyo, Japan.
- Penna MLF Epidemiology and Biostatistics Department, Universidade Federal Fluminense, Rio de Janeiro, Brazil.
- Cole ST Global Health Institute, École Polytechnique Fédérale de Lausanne, Switzerland.
- Penna GO Tropical Medicine Centre, University of Brasília, Brasília DF, Brazil.
- 2017-06-16
Published in:
- PLoS neglected tropical diseases. - 2017
Adolescent
Adult
Brazil
Computational Biology
DNA, Bacterial
Genome, Bacterial
High-Throughput Nucleotide Sequencing
Humans
Leprosy
Male
Molecular Typing
Mycobacterium leprae
Randomized Controlled Trials as Topic
Recurrence
Sequence Analysis, DNA
Young Adult
English
BACKGROUND
Since leprosy is both treated and controlled by multidrug therapy (MDT) it is important to monitor recurrent cases for drug resistance and to distinguish between relapse and reinfection as a means of assessing therapeutic efficacy. All three objectives can be reached with single nucleotide resolution using next generation sequencing and bioinformatics analysis of Mycobacterium leprae DNA present in human skin.
METHODOLOGY
DNA was isolated by means of optimized extraction and enrichment methods from samples from three recurrent cases in leprosy patients participating in an open-label, randomized, controlled clinical trial of uniform MDT in Brazil (U-MDT/CT-BR). Genome-wide sequencing of M. leprae was performed and the resultant sequence assemblies analyzed in silico.
PRINCIPAL FINDINGS
In all three cases, no mutations responsible for resistance to rifampicin, dapsone and ofloxacin were found, thus eliminating drug resistance as a possible cause of disease recurrence. However, sequence differences were detected between the strains from the first and second disease episodes in all three patients. In one case, clear evidence was obtained for reinfection with an unrelated strain whereas in the other two cases, relapse appeared more probable.
CONCLUSIONS/SIGNIFICANCE
This is the first report of using M. leprae whole genome sequencing to reveal that treated and cured leprosy patients who remain in endemic areas can be reinfected by another strain. Next generation sequencing can be applied reliably to M. leprae DNA extracted from biopsies to discriminate between cases of relapse and reinfection, thereby providing a powerful tool for evaluating different outcomes of therapeutic regimens and for following disease transmission.
Since leprosy is both treated and controlled by multidrug therapy (MDT) it is important to monitor recurrent cases for drug resistance and to distinguish between relapse and reinfection as a means of assessing therapeutic efficacy. All three objectives can be reached with single nucleotide resolution using next generation sequencing and bioinformatics analysis of Mycobacterium leprae DNA present in human skin.
METHODOLOGY
DNA was isolated by means of optimized extraction and enrichment methods from samples from three recurrent cases in leprosy patients participating in an open-label, randomized, controlled clinical trial of uniform MDT in Brazil (U-MDT/CT-BR). Genome-wide sequencing of M. leprae was performed and the resultant sequence assemblies analyzed in silico.
PRINCIPAL FINDINGS
In all three cases, no mutations responsible for resistance to rifampicin, dapsone and ofloxacin were found, thus eliminating drug resistance as a possible cause of disease recurrence. However, sequence differences were detected between the strains from the first and second disease episodes in all three patients. In one case, clear evidence was obtained for reinfection with an unrelated strain whereas in the other two cases, relapse appeared more probable.
CONCLUSIONS/SIGNIFICANCE
This is the first report of using M. leprae whole genome sequencing to reveal that treated and cured leprosy patients who remain in endemic areas can be reinfected by another strain. Next generation sequencing can be applied reliably to M. leprae DNA extracted from biopsies to discriminate between cases of relapse and reinfection, thereby providing a powerful tool for evaluating different outcomes of therapeutic regimens and for following disease transmission.
- Language
-
- English
- Open access status
- gold
- Identifiers
-
- DOI 10.1371/journal.pntd.0005598
- PMID 28617800
- Persistent URL
- https://sonar.ch/global/documents/105567
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