Diversity and disease pathogenesis in Mycobacterium tuberculosis

doi:10.1016/j.tim.2014.10.005

Trends in Microbiology

Volume 23, Issue 1, January 2015, Pages 14-21

https://doi.org/10.1016/j.tim.2014.10.005 Get rights and content

Highlights

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Mycobacterium tuberculosis was historically associated with limited genotypic diversity.
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Recent evidence suggests infecting bacillary populations are more diverse than previously thought.
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We consider the consequences of diversity for mycobacterial pathogenesis.
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Diversity enables exploration of fitness landscapes while retaining core functions.
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Systems biology approaches must be developed to understand TB.

The increasing availability of whole-genome sequence (WGS) data for Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB), suggests that circulating genotypes have been molded by three dominant evolutionary forces: long-term persistence within the human population, which requires a core programme of infection, disease, and transmission; selective pressure on specific genomic loci, which provides evidence of lineage-specific adaptation to host populations; and drug exposure, which has driven the rapid emergence of resistant isolates following the global implementation of anti-TB chemotherapy. Here, we provide an overview of these factors in considering the implications of genotypic diversity for disease pathogenesis, vaccine efficacy, and drug treatment.

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).

References (79)

A. Zumla
WHO's 2013 global report on tuberculosis: successes, threats, and opportunities
Lancet
(2013)
P.R. McAdam
High-throughput sequencing for the study of bacterial pathogen biology
Curr. Opin. Microbiol.
(2014)
D. Stucki et al.
Single nucleotide polymorphisms in Mycobacterium tuberculosis and the need for a curated database
Tuberculosis
(2013)
J.M. Bryant
Whole-genome sequencing to establish relapse or re-infection with Mycobacterium tuberculosis: a retrospective observational study
Lancet Respir. Med.
(2013)
T.M. Walker
Whole-genome sequencing to delineate Mycobacterium tuberculosis outbreaks: a retrospective observational study
Lancet Infect. Dis.
(2013)
B.D. Robertson
Detection and treatment of subclinical tuberculosis
Tuberculosis
(2012)
N.J. Saunders
Deep resequencing of serial sputum isolates of Mycobacterium tuberculosis during therapeutic failure due to poor compliance reveals stepwise mutation of key resistance genes on an otherwise stable genetic background
J. Infect.
(2011)
D. Brites et al.
Old and new selective pressures on Mycobacterium tuberculosis
Infect. Genet. Evol.
(2012)
D.G. Russell
The evolutionary pressures that have molded Mycobacterium tuberculosis into an infectious adjuvant
Curr. Opin. Microbiol.
(2013)
Z. Yang
How dormant is Mycobacterium tuberculosis during latency? A study integrating genomics and molecular epidemiology
Infect. Genet. Evol.
(2011)

A. O’Garra

The immune response in tuberculosis

Annu. Rev. Immunol.

(2013)

P.L. Lin

Sterilization of granulomas is common in active and latent tuberculosis despite within-host variability in bacterial killing

Nat. Med.

(2014)

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2023, Molecular Medical Microbiology, Third Edition
Mycobacterium tuberculosis is the causative pathogen of tuberculosis (TB), an ancient disease that continues to tremendously impact global human health. Rapid and accurate diagnosis, access to effective therapies, and population-wise vaccination programs are essential to eliminate the global TB pandemic. Recent progresses in TB research have advanced the understanding of microbial pathogenesis, leading to the generation of new diagnostics and therapeutics. The application of molecular-based diagnostic tools is rapidly changing the way TB diagnosis is approached globally. In parallel, antibiotics and vaccines under research and development have exhibited potential in facilitating TB control, which still urgently needs improved efficacy.
Human tuberculosis and Mycobacterium tuberculosis complex: A review on genetic diversity, pathogenesis and omics approaches in host biomarkers discovery
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Citation Excerpt :
This linkage could be further associated with differential transmission efficacy, depending on host populations under certain conditions (Gagneux et al., 2006; Fenner et al., 2013). An analysis of a massive collection of MTBC strains by DNA sequencing also suggests the expansion of genetic diversity in human- adapted MTBC is related to human migration (Warner et al., 2015). Comas et al. (2010)reported that a large number of T-cell epitopes of M. tuberculosis across different lineages are highly conserved and remain unchanged, suggesting the presence of a robust selection pressure to avoid M. tuberculosis from being recognized by T cells.
Mycobacterium tuberculosis complex (MTBC) refers to a group of mycobacteria encompassing nine members of closely related species that causes tuberculosis in animals and humans. Among the nine members, Mycobacterium tuberculosis (M. tuberculosis) remains the main causative agent for human tuberculosis that results in high mortality and morbidity globally. In general, MTBC species are low in diversity but exhibit distinctive biological differences and phenotypes among different MTBC lineages. MTBC species are likely to have evolved from a common ancestor through insertions/deletions processes resulting in species speciation with different degrees of pathogenicity. The pathogenesis of human tuberculosis is complex and remains poorly understood. It involves multi-interactions or evolutionary co-options between host factors and bacterial determinants for survival of the MTBC. Granuloma formation as a protection or survival mechanism in hosts by MTBC remains controversial. Additionally, MTBC species are capable of modulating host immune response and have adopted several mechanisms to evade from host immune attack in order to survive in humans. On the other hand, current diagnostic tools for human tuberculosis are inadequate and have several shortcomings. Numerous studies have suggested the potential of host biomarkers in early diagnosis of tuberculosis, in disease differentiation and in treatment monitoring. “Multi-omics” approaches provide holistic views to dissect the association of MTBC species with humans and offer great advantages in host biomarkers discovery. Thus, in this review, we seek to understand how the genetic variations in MTBC lead to species speciation with different pathogenicity. Furthermore, we also discuss how the host and bacterial players contribute to the pathogenesis of human tuberculosis. Lastly, we provide an overview of the journey of “omics” approaches in host biomarkers discovery in human tuberculosis and provide some interesting insights on the challenges and directions of “omics” approaches in host biomarkers innovation and clinical implementation.
Genetic diversity of the Mycobacterium tuberculosis complex strains from newly diagnosed tuberculosis patients in Northwest Ethiopia reveals a predominance of East-African-Indian and Euro-American lineages
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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.
This study described the population structure of M. tuberculosis complex (MTBc) strains among patients with pulmonary or lymph node tuberculosis (TB) in Northwest Ethiopia and tested the performance of culture isolation and MPT64-based speciation for Lineage 7 (L7).
Patients were recruited between April 2017 and June 2019 in North Gondar, Ethiopia. The MPT64 assay was used to confirm MTBc, and spoligotyping was used to characterize mycobacterial lineages. Line probe assay (LPA) was used to detect resistance to rifampicin and isoniazid.
Among 274 MTBc genotyped isolates, there were five MTBc lineages: L1–L4 and L7 were identified, with predominant East-African-Indian (L3) (53.6%) and Euro-American (L4) (40.1%) strains, and low prevalence (2.6%) of Ethiopia L7. The genotypes were similarly distributed between pulmonary and lymph node TB, and all lineages were equally isolated by culture and recognized as MTBc by the MPT64 assay. Additionally, LPA showed that 259 (94.5%) MTBc were susceptible to both rifampicin and isoniazid, and one (0.4%) was multi-drug resistant (resistant to both rifampicin and isoniazid).
These findings show that TB in North Gondar, Ethiopia, is mainly caused by L3 and L4 strains, with low rates of L7, confirmed as MTBc by MPT64 assay and with limited resistance to rifampicin and isoniazid.
Towards better prediction of Mycobacterium tuberculosis lineages from MIRU-VNTR data
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Citation 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).
The determination of lineages from strain-based molecular genotyping information is an important problem in tuberculosis. Mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) typing is a commonly used molecular genotyping approach that uses counts of the number of times pre-specified loci repeat in a strain. There are three main approaches for determining lineage based on MIRU-VNTR data - one based on a direct comparison to the strains in a curated database, and two others, on machine learning algorithms trained on a large collection of labeled data.
All existing methods have limitations. The direct approach imposes an arbitrary threshold on how much a database strain can differ from a given one to be informative. On the other hand, the machine learning-based approaches require a substantial amount of labeled data. Notably, all three methods exhibit suboptimal classification accuracy without additional data.
We explore several computational approaches to address these limitations. First, we show that eliminating the arbitrary threshold improves the performance of the direct approach. Second, we introduce RuleTB, an alternative direct method that proposes a concise set of rules for determining lineages. Lastly, we propose StackTB, a machine learning approach that requires only a fraction of the training data to outperform the accuracy of both existing machine learning methods.
Our approaches demonstrate superior performance on a training dataset collected in New York City over 10 years, and the improvement in performance translates to a held-out testing set. We conclude that our methods provide opportunities for improving the determination of pathogenic lineages based on MIRU-VNTR data.
Mce-associated protein Rv0177 alters the cell wall structure of Mycobacterium smegmatis and promotes macrophage apoptosis via regulating the cytokines
2019, International Immunopharmacology
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Tuberculosis (TB) caused by Mycobacterium tuberculosis remains a formidable threat to the global public health with millions of deaths and around 9 million of infections each year [1]. M. tuberculosis virulence factors have been extensively characterized [2–6]. However, the roles of the mce operons still remain elusive although several mce proteins are reported to be involved in the pathogenesis of M. tuberculosis.
The success of Mycobacterium tuberculosis as a pathogen largely contributes to its ability to infect, modify and persist within the host cells. M. tuberculosis Rv0177 is a gene of the mce1 operon (Mammalian cell entry), encoding a conserved hypothetical protein, essential for M. tuberculosis survival and up-regulated within murine macrophages. To explore its function, Rv0177 was heterologously expressed in M. smegmatis. The recombinant protein was located in the cell wall. M. smegmatis recombinant strain expressing Rv0177 altered sliding motility, its cell wall architecture and the permeability. Moreover, M. smegmatis expressing Rv0177 could up-regulate MCP-1 and downregulate the IL-6 expression in RAW264.7 macrophages in comparison to the control. MS_Rv0177 increased the expression of MCP-1 inducible protein (MCPIP) and a C/EBP homologous protein (CHOP) owing to MCP-1. In addition, the JNK signaling pathway was engaged in the interplay between MS_Rv0177 and macrophages. The macrophage caspase-3 activation and cell apoptosis were induced by the recombinant. This provided novel functional cues for the MCE-associated Rv0177.
Whole genome sequencing for the management of drug-resistant TB in low income high TB burden settings: Challenges and implications
2017, Tuberculosis
Citation 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].
Drug-resistant tuberculosis is emerging as a major global health challenge, fuelled by a limited formulary and reduced ability to timeously diagnose resistance. Furthermore, poorly managed drug-resistant tuberculosis is complicated by poor treatment outcomes and high rates of morbidity and mortality. A rapid diagnosis together with individualized management are essential in order to limit disease and curtail transmission. Recently, the feasibility of Whole Genome Sequencing (WGS) technology for the routine diagnosis and drug susceptibility testing of Mycobacterium Tuberculosis in a high income, low tuberculosis burden setting, was demonstrated. However, the use of WGS in low income settings, with the highest burden of disease, has not been evaluated. This viewpoint highlights the challenges and implications associated with the use of Whole Genome Sequencing for the diagnosis and management of drug-resistant tuberculosis in such settings.

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Trends in Microbiology

ReviewDiversity and disease pathogenesis in Mycobacterium tuberculosis

Highlights

Section snippets

Genetic diversity in the Mycobacterium tuberculosis complex

The M. tuberculosis infection cycle

Evidence for microdiversity

What are the implications of genotypic diversity for pathogenesis?

Evidence for a conserved interaction between host and pathogen

Genotype–phenotype variability in a host-adapted pathogen

Implications of genotypic diversity: transmission of hypervirulent strains

What are the processes underlying genome dynamics in M. tuberculosis?

Linking strain genotypes with disease phenotypes

Concluding remarks: approaching a systems biology of TB

Acknowledgments

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Host-pathogen coevolution in human tuberculosis

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Whole-genome sequencing for rapid susceptibility testing of M. tuberculosis

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Mycobacterium tuberculosis growth at the cavity surface: a microenvironment with failed immunity

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The origins of a 350-kilobase genomic duplication in Mycobacterium tuberculosis and its impact on virulence

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The immune response in tuberculosis

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Review
Diversity and disease pathogenesis in Mycobacterium tuberculosis