Chapter 22 : Evolution of : New Insights into Pathogenicity and Drug Resistance

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The evolution of toward one of the most dangerous human pathogens is of particular interest for the analysis of the continued importance of tuberculosis as a global disease. While the majority of mycobacterial species are harmless environmental bacteria, is able to induce pulmonary lesions and disease in the human host, which represents an essential step for the aerosol transmission of the bacterium to new individuals. The question of when and where or one of its progenitors has acquired this faculty has interested scientists for years. It is hypothesized that the ancestors of once had an environmental reservoir and gradually evolved to adapt to the life within host cells, leading finally to the feature of getting transmitted from one host to another ( ). First insights into this issue can be obtained from genomic comparison of with related nontuberculous mycobacteria (NTM), also known as atypical mycobacteria or mycobacteria other than tuberculosis (MOTT). Based on 16S rRNA sequence similarity, and were the currently known closest relatives of ( ). In a later study, based on whole-genome sequencing (WGS), was found as the closest NTM species of ( ), whereas a different WGS study designated / as most closely related to , followed by a subgroup containing , , and ( ). However, despite the similarities at the DNA and protein level, the genome size differences between the closest NTM species relative to are considerable ( ). strains harbor a 4.4 MB genome ( ), whereas the genomes of , , and are larger in size (6.7, 6.4, and 5.8 MB, respectively) ( ). In contrast, the genomes of , , and are smaller in size (4.2, 3.3, and 3.3 MB, respectively) ( ), whereby the strong size reduction of the latter two species is due to a common, extensive phase of reductive evolution ( ). It seems conceivable that the individual adaptations of the different mycobacterial species to specific environmental conditions went along with genome downsizing, gene acquisition through horizontal gene transfer, genome rearrangements, and/or recombination.

Citation: Boritsch E, Brosch R. 2017. Evolution of : New Insights into Pathogenicity and Drug Resistance, p 495-515. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0020-2016
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Figure 1

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 .

Citation: Boritsch E, Brosch R. 2017. Evolution of : New Insights into Pathogenicity and Drug Resistance, p 495-515. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0020-2016
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Image of Figure 2
Figure 2

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 ). The filtered SNPs refer to the mutations identified between the various strains relative to H37Rv ( ). Figure reproduced from reference .

Citation: Boritsch E, Brosch R. 2017. Evolution of : New Insights into Pathogenicity and Drug Resistance, p 495-515. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0020-2016
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Figure 3

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 ( ).

Citation: Boritsch E, Brosch R. 2017. Evolution of : New Insights into Pathogenicity and Drug Resistance, p 495-515. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0020-2016
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Figure 4

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 .

Citation: Boritsch E, Brosch R. 2017. Evolution of : New Insights into Pathogenicity and Drug Resistance, p 495-515. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0020-2016
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