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Evolution of : New Insights into Pathogenicity and Drug Resistance

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  • Authors: Eva C. Boritsch1, Roland Brosch2
  • Editors: William R. Jacobs Jr.3, Helen McShane4, Valerie Mizrahi5, Ian M. Orme6
    Affiliations: 1: Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, 75015 Paris, France; 2: Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, 75015 Paris, France; 3: Howard Hughes Medical Institute, Albert Einstein School of Medicine, Bronx, NY 10461; 4: University of Oxford, Oxford OX3 7DQ, United Kingdom; 5: University of Cape Town, Rondebosch 7701, South Africa; 6: Colorado State University, Fort Collins, CO 80523
  • Source: microbiolspec October 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.TBTB2-0020-2016
  • Received 07 June 2016 Accepted 01 August 2016 Published 28 October 2016
  • R. Brosch, [email protected]
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  • Abstract:

    The tuberculosis agent has undergone a long and selective evolution toward human infection and represents one of the most widely spread pathogens due to its efficient aerosol-mediated human-to-human transmission. With the availability of more and more genome sequences, the evolutionary trajectory of this obligate pathogen becomes visible, which provides us with new insights into the molecular events governing evolution of the bacterium and its ability to accumulate drug-resistance mutations. In this review, we summarize recent developments in mycobacterial research related to this matter that are important for a better understanding of the current situation and future trends and developments in the global epidemiology of tuberculosis, as well as for possible public health intervention possibilities.

  • Citation: Boritsch E, Brosch R. 2016. Evolution of : New Insights into Pathogenicity and Drug Resistance. Microbiol Spectrum 4(5):TBTB2-0020-2016. doi:10.1128/microbiolspec.TBTB2-0020-2016.


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The tuberculosis agent has undergone a long and selective evolution toward human infection and represents one of the most widely spread pathogens due to its efficient aerosol-mediated human-to-human transmission. With the availability of more and more genome sequences, the evolutionary trajectory of this obligate pathogen becomes visible, which provides us with new insights into the molecular events governing evolution of the bacterium and its ability to accumulate drug-resistance mutations. In this review, we summarize recent developments in mycobacterial research related to this matter that are important for a better understanding of the current situation and future trends and developments in the global epidemiology of tuberculosis, as well as for possible public health intervention possibilities.

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Scheme showing supposed molecular key events in mycobacterial evolution from a recombinogenic strain pool toward professional pathogens of mammalian hosts. Network phylogeny inferred among eight strains and 46 selected genome sequences from MTBC members by NeighborNet analysis. Pairwise alignments of whole genome SNP data are the basis of the calculation. Recombination of and deletion of in a potential progenitor of the MTBC strains illustrated in the inset. Figure reproduced from reference 44 .

Source: microbiolspec October 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.TBTB2-0020-2016
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Neighbor-joining phylogeny scheme based on variable nucleotide positions with main focus on tubercle bacilli that have a human host preference, using as root of the tree (after reference 56 ). The filtered SNPs refer to the mutations identified between the various strains relative to H37Rv ( 15 ). Figure reproduced from reference 40 .

Source: microbiolspec October 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.TBTB2-0020-2016
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Overview of a large number of potential drug resistance as well as compensatory mutations against first- and second-line drugs. Mutations shown in bold represent most commonly found mutations among resistant strains. Semibold secondary mutations in , and were found to be shared by related strains, thus suggesting mutations favoring transmission. Any mutations leading to at least rifampin and isoniazid resistance confer an MDR phenotype, whereas MDR strains with additional mutations against at least one of the three injectable drugs, kanamycin, amikacin, and capreomycin, and to any fluoroquinolone used against are referred to as XDR strains. Table based on mutations found in the following publications ( 50 , 58 , 73 , 89 , 91 , 92 , 130 , 133 , 142 , 143 , 149 , 151 154 , 156 , 163 , 166 ).

Source: microbiolspec October 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.TBTB2-0020-2016
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Overview of a large number of potential drug resistance as well as compensatory mutations against first- and second-line drugs. Mutations shown in bold represent most commonly found mutations among resistant strains. Semibold secondary mutations in , and were found to be shared by related strains, thus suggesting mutations favoring transmission. Any mutations leading to at least rifampin and isoniazid resistance confer an MDR phenotype, whereas MDR strains with additional mutations against at least one of the three injectable drugs, kanamycin, amikacin, and capreomycin, and to any fluoroquinolone used against are referred to as XDR strains. Table based on mutations found in the following publications ( 50 , 58 , 73 , 89 , 91 , 92 , 130 , 133 , 142 , 143 , 149 , 151 154 , 156 , 163 , 166 ).

Source: microbiolspec October 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.TBTB2-0020-2016
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Suggested model for a selection bottleneck followed by random mutations on the population structure of clinical isolates. Genetic diversity of subpopulations is present in a rifampin monoresistant clinical isolate (each individual bacterium contains a rifampin resistance-conferring mutation). Upon isoniazid treatment clones carrying low-cost resistance mutations to the drug become dominant and prevail over other variants, resulting in the loss of numerous other genetic mutations. Subsequent repeated genetic diversification results in genomic heterogeneity of the MDR strain population. x represents an isoniazid resistance-causing mutation. Figure adapted from reference 163 .

Source: microbiolspec October 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.TBTB2-0020-2016
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