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      Phylogenomics and antimicrobial resistance of the leprosy bacillus Mycobacterium leprae

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      1 , 1 , 1 , 2 , 1 , 3 , 4 , 1 , 5 , 6 , 7 , 4 , 8 , 8 , 8 , 9 , 9 , 10 , 11 , 12 , 1 , 13 , 13 , 13 , 14 , 15 , 16 , 17 , 18 , 18 , 18 , 19 , 19 , 12 , 20 , 5 , 21 , 11 , 11 , 22 , 22 , 23 , 4 , 6 , 6 , 1 ,
      Nature Communications
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          Abstract

          Leprosy is a chronic human disease caused by the yet-uncultured pathogen Mycobacterium leprae. Although readily curable with multidrug therapy (MDT), over 200,000 new cases are still reported annually. Here, we obtain M. leprae genome sequences from DNA extracted directly from patients’ skin biopsies using a customized protocol. Comparative and phylogenetic analysis of 154 genomes from 25 countries provides insight into evolution and antimicrobial resistance, uncovering lineages and phylogeographic trends, with the most ancestral strains linked to the Far East. In addition to known MDT-resistance mutations, we detect other mutations associated with antibiotic resistance, and retrace a potential stepwise emergence of extensive drug resistance in the pre-MDT era. Some of the previously undescribed mutations occur in genes that are apparently subject to positive selection, and two of these ( ribD, fadD9) are restricted to drug-resistant strains. Finally, nonsense mutations in the nth excision repair gene are associated with greater sequence diversity and drug resistance.

          Abstract

          Leprosy is caused by the yet-uncultured pathogen Mycobacterium leprae. Here, Benjak et al. obtain M. leprae genome sequences from DNA extracted from patients' skin biopsies and, by analysing 154 genomes from 25 countries, provide insight into the pathogen’s evolution and antimicrobial resistance.

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          Most cited references47

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          The continuing challenges of leprosy.

          Leprosy is best understood as two conjoined diseases. The first is a chronic mycobacterial infection that elicits an extraordinary range of cellular immune responses in humans. The second is a peripheral neuropathy that is initiated by the infection and the accompanying immunological events. The infection is curable but not preventable, and leprosy remains a major global health problem, especially in the developing world, publicity to the contrary notwithstanding. Mycobacterium leprae remains noncultivable, and for over a century leprosy has presented major challenges in the fields of microbiology, pathology, immunology, and genetics; it continues to do so today. This review focuses on recent advances in our understanding of M. leprae and the host response to it, especially concerning molecular identification of M. leprae, knowledge of its genome, transcriptome, and proteome, its mechanisms of microbial resistance, and recognition of strains by variable-number tandem repeat analysis. Advances in experimental models include studies in gene knockout mice and the development of molecular techniques to explore the armadillo model. In clinical studies, notable progress has been made concerning the immunology and immunopathology of leprosy, the genetics of human resistance, mechanisms of nerve injury, and chemotherapy. In nearly all of these areas, however, leprosy remains poorly understood compared to other major bacterial diseases.
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            The competitive cost of antibiotic resistance in Mycobacterium tuberculosis.

            Mathematical models predict that the future of the multidrug-resistant tuberculosis epidemic will depend on the fitness cost of drug resistance. We show that in laboratory-derived mutants of Mycobacterium tuberculosis, rifampin resistance is universally associated with a competitive fitness cost and that this cost is determined by the specific resistance mutation and strain genetic background. In contrast, we demonstrate that prolonged patient treatment can result in multidrug-resistant strains with no fitness defect and that strains with low- or no-cost resistance mutations are also the most frequent among clinical isolates.
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              Learning how to live together: genomic insights into prokaryote-animal symbioses.

              Our understanding of prokaryote-eukaryote symbioses as a source of evolutionary innovation has been rapidly increased by the advent of genomics, which has made possible the biological study of uncultivable endosymbionts. Genomics is allowing the dissection of the evolutionary process that starts with host invasion then progresses from facultative to obligate symbiosis and ends with replacement by, or coexistence with, new symbionts. Moreover, genomics has provided important clues on the mechanisms driving the genome-reduction process, the functions that are retained by the endosymbionts, the role of the host, and the factors that might determine whether the association will become parasitic or mutualistic.
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                Author and article information

                Contributors
                stewart.cole@epfl.ch
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                24 January 2018
                24 January 2018
                2018
                : 9
                : 352
                Affiliations
                [1 ]ISNI 0000000121839049, GRID grid.5333.6, Global Health Institute, , Ecole Polytechnique Fédérale de Lausanne, ; Lausanne, 1015 Switzerland
                [2 ]ISNI 0000 0001 2154 7601, GRID grid.411494.d, Department of Microbiology and Biotechnology Centre, , Maharaja Sayajirao University of Baroda, ; Vadodara, 390002 India
                [3 ]ISNI 0000 0004 0587 0574, GRID grid.416786.a, Swiss Tropical and Public Health Institute, ; 4051 Basel, Switzerland
                [4 ]ISNI 0000 0000 4319 4715, GRID grid.418720.8, Armauer Hansen Research Institute, ; PO Box 1005, Addis Ababa, 1000 Ethiopia
                [5 ]ISNI 0000 0001 0723 0931, GRID grid.418068.3, Laboratory of Molecular Biology Applied to Mycobacteria, , Oswaldo Cruz Institute, ; Fiocruz, Rio de Janeiro, 21040-360 Brazil
                [6 ]ISNI 0000 0001 2220 1880, GRID grid.410795.e, Leprosy Research Center, , National Institute of Infectious Diseases, ; Higashimurayama, Tokyo, 189-0002 Japan
                [7 ]AUEN Polyclinic, Nakatomi, Tokorozawa, 359-0002 Saitama Prefecture Japan
                [8 ]ISNI 0000 0001 2171 5249, GRID grid.271300.7, Laboratório de Dermato-Imunologia, Instituto de Ciências Biológicas, , Universidade Federal do Pará, ; Marituba, 67200-000 Pará Brazil
                [9 ]ISNI 0000 0004 1937 0722, GRID grid.11899.38, Dermatology Division, Ribeirão Preto Medical School, , University of São Paulo, ; Ribeirão Preto, 14049-900 São Paulo Brazil
                [10 ]ISNI 0000 0001 2171 5249, GRID grid.271300.7, Spatial Epidemiology Laboratory, , Federal University of Pará, ; Castanhal, 68746-360 Pará Brazil
                [11 ]ISNI 0000 0001 0723 0931, GRID grid.418068.3, Leprosy Laboratory, , Oswaldo Cruz Institute, ; Fiocruz, Rio de Janeiro, 21040-900 Brazil
                [12 ]ISNI 0000 0001 2192 5801, GRID grid.411195.9, Tropical Pathology and Public Health Institute, , Federal University of Goiás, ; Goiânia, 74605-050 Brazil
                [13 ]Ministry of Health and Population, c/o National Leprosy Elimination Programme, Taiz, Yemen
                [14 ]ISNI 0000 0004 1936 973X, GRID grid.5252.0, Division of Infectious Diseases and Tropical Medicine, University Hospital, , Ludwig-Maximilians-University, ; 80802 Munich, Germany
                [15 ]ISNI 0000 0001 2203 0321, GRID grid.411455.0, Laboratorio Interdisciplinario de Investigación Dermatológica, Servicio de Dermatología, Hospital Universitario, , Universidad Autónoma de Nuevo León, ; 64460 Monterrey, Mexico
                [16 ]Programme National Lèpre de Guinée, Conakry, Guinea
                [17 ]ISNI 0000 0001 0382 0205, GRID grid.412037.3, Centre Interfacultaire de Formation et de Recherche en Environnement pour le Développement Durable, , University of Abomey-Calavi, ; 03 BP 1463 Jericho, Cotonou Benin
                [18 ]Centre National d’Appui à la Lutte Contre la Maladie, Bamako, Mali
                [19 ]Programme National de Lutte contre la Lèpre, Ministry of Public Health, Niamey, Niger
                [20 ]ISNI 0000 0001 2238 5157, GRID grid.7632.0, Tropical Medicine Centre, , University of Brasília, ; Fiocruz, Brasília, 70910-900 Brazil
                [21 ]Department of Biomedical Sciences, Mycobacteriology Unit, Tropical Institute of Medicine, 2000 Antwerp, Belgium
                [22 ]Lauro Souza Lima Institute, Bauru, 17034-971 São Paulo Brazil
                [23 ]ISNI 0000 0004 1936 8083, GRID grid.47894.36, Department of Microbiology, Immunology, and Pathology, , Colorado State University, ; Fort Collins, CO 80523-1682 USA
                Author information
                http://orcid.org/0000-0003-4522-6575
                http://orcid.org/0000-0003-4889-2784
                http://orcid.org/0000-0002-8028-1150
                Article
                2576
                10.1038/s41467-017-02576-z
                5783932
                29367657
                d4b3c117-8791-4d32-a4c5-48d273ed4b93
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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                : 25 August 2017
                : 12 December 2017
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