Trends in Microbiology
ReviewDiversity and disease pathogenesis in Mycobacterium tuberculosis
Section snippets
Genetic diversity in the Mycobacterium tuberculosis complex
TB is a global problem, with recent reports estimating approximately 8.6 million new cases and 1.3 million deaths annually [1]. This is despite the existence of effective frontline combination chemotherapy, a widely administered vaccine, and the allocation over the past decade of massive resources to develop improved interventions 2, 3. Co-infection with HIV, and the emergence of drug resistance have amplified the problem; however, these represent relatively recent, or ‘modern’ (Figure 1),
The M. tuberculosis infection cycle
As an obligate pathogen, the persistence of M. tuberculosis within the human population depends on the ability to drive successive cycles of infection, disease (in some cases, subclinical TB [17] followed by reactivation), and transmission. The reliance on a single host species necessarily exposes the infecting pathogen to multiple potential evolutionary cul-de-sacs that might arise as a consequence of the elimination of the bacillus (clearance) or the demise of the organism within an infected
Evidence for microdiversity
Numerous studies have identified significant genotypic diversity within bacilli isolated from single hosts 14, 22, 23, 24, 25. In some cases, this has been attributed to mixed infection with two distinct strains 14, 22, a phenomenon that is likely to occur in high-burden settings with an elevated force of infection 26, 27 and, importantly, suggests the potential for direct competition between infecting genotypes. In addition, there is increasing evidence of microdiversity within M. tuberculosis
What are the implications of genotypic diversity for pathogenesis?
The natural lifecycle of M. tuberculosis suggests a further explanation for the apparent discrepancy between the relative genetic stability of transmitted strains and the potential intrapatient diversity. Mycobacterium tuberculosis is transmitted in infectious aerosols, which are inhaled deep into the lung where the bacilli lodge in alveoli and are engulfed by resident macrophages. Although the precise details remain to be determined, it is assumed that successful transmission from a prevalent
Evidence for a conserved interaction between host and pathogen
The contention that coevolution might have resulted in a core M. tuberculosis–host interaction is supported by several observations that derive from independent analyses of both bacillary and host genotypes and functions. For example, a key study [41] showed that T cell epitopes are highly conserved across M. tuberculosis lineages, suggesting that selective pressure acts against sequence diversity in immunogenic regions. This is reinforced by a more recent analysis [42] that revealed that
Genotype–phenotype variability in a host-adapted pathogen
Given the significant bottlenecks to allelic fixation within the M. tuberculosis population, what factors drive the spread of SNPs not associated with drug resistance? A recent study conducted in a low-density setting indicated that there is a sympatric relation between specific M. tuberculosis strains and cognate hosts [49], suggesting that host genotypes have some influence on bacillary diversity. However, in high-density settings with significant bacterial and host genomic diversity, there
Implications of genotypic diversity: transmission of hypervirulent strains
The conserved host–pathogen interaction proposed above assumes that M. tuberculosis is primarily infecting immune competent individuals. As noted elsewhere [54], a functional adaptive immune response is essential for M. tuberculosis to complete its lifecycle. When infection and disease occur against a background of compromised immunity, TB disease manifestation and, therefore, the infection cycle, are corrupted, consistent with the finding that HIV-positive individuals are poor TB transmitters
What are the processes underlying genome dynamics in M. tuberculosis?
The observed intrapatient microdiversity implies that the M. tuberculosis mutation rate might be elevated during host infection, a possibility that has also been invoked to explain the emergence of multidrug resistance in the presence of combination therapy (reviewed in [30]). To date, however, evidence from both animal [57] and human studies [58] suggests that, during active disease, mutations accumulate at rates that are within the ranges calculated in vitro. Determining the mutation rate
Linking strain genotypes with disease phenotypes
The complex genotypes associated with drug resistance 35, 36, as well as emerging evidence of the impact of compensatory mutations on the acquisition and maintenance of resistance alleles [32], highlight the importance of determining epistatic interactions. For those mutations that occur in the absence of drug resistance, it is even more challenging to determine the functional consequences of different mutations: as noted elsewhere [11], the absence of HGT means that all SNPs in an individual
Concluding remarks: approaching a systems biology of TB
Mycobacterium tuberculosis has a 4.4-Mb genome that harbors evidence of the reductive evolution characteristic of an obligate pathogen 4, 65; however, the bacillus remains a formidable prototroph capable of colonizing diverse host environments and resisting the associated stresses. We have argued here that at least part of the success of the organism appears to reside in the stable interaction with its obligate human host while retaining the capacity to generate phenotypic diversity.
Acknowledgments
We apologize to all those authors whose work was not cited owing to space limitations. We acknowledge funding from the South African Medical Research Council (SA MRC), the National Research Foundation of South Africa, and the Howard Hughes Medical Institute (Senior International Research Scholar's grant to V.M.). Work in our laboratory on TB transmission is funded by the SA MRC with funds from National Treasury under the Economic Competitiveness and Support Package (MRC-RFA-UFSP-01-2013/CCAMP).
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2021, International Journal of Infectious DiseasesCitation Excerpt :Today, eight phylogenetic lineages of the MTBc have been identified worldwide, causing TB in humans (Gagneux et al., 2006; Firdessa et al., 2013; Ngabonziza et al., 2020). The distribution of MTBc lineages has shown significant geographical variation (Gagneux et al., 2006; Gagneux and Small, 2007), with a major impact on disease presentation, drug resistance nature and host adaptation (Ford et al., 2013; Warner et al., 2015). A high rate of lymph node TB has been reported in Ethiopia (Berg et al., 2015; Biadglegne et al., 2015; Tadesse et al., 2017), and the country uniquely harbors M. tuberculosis Lineage 7 (Firdessa et al., 2013; Comas et al., 2015), a lineage in-between ‘ancestral’ and ‘modern’ MTBc members.
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2019, Infection, Genetics and EvolutionCitation Excerpt :The genetic diversity of the infectious pathogen Mycobacterium tuberculosis has played an important role in its adaptation to its diverse host species, including humans (Hershberg et al., 2008; Gagneux, 2012; Warner et al., 2015).
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2017, TuberculosisCitation Excerpt :Bacterial factors such as spontaneous mutations in the Mtb genome that block the target site for drug binding (e.g., mutations in the rpoB gene and gyrA/B genes that confer resistance to rifampicin (RIF) and the fluoroquinolones respectively), interfere with pro-drug activation (e.g., mutations in the katG and fgd gene that confer resistance to isoniazid (INH) and PA-824 respectively), or induce overexpression of the target site (e.g., the promoter region of inhA that confers resistance to INH/ethionamide) have been described [8]. In addition, WGS has defined many novel mutations associated with drug resistance and has recently demonstrated that new mutations can arise multiple times within an individual failing anti-TB therapy [9] [10,11]. It is well acknowledged that WGS has contributed to improved understanding of the pathogenesis, immunology, evolution and transmission of TB [4,12].