Review
Global phylogeography of Mycobacterium tuberculosis and implications for tuberculosis product development

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Summary

New tools for controlling tuberculosis are urgently needed. Despite our emerging understanding of the biogeography of Mycobacterium tuberculosis, the implications for development of new diagnostics, drugs, and vaccines is unknown. M tuberculosis has a clonal genetic population structure that is geographically constrained. Evidence suggests strain-specific differences in virulence and immunogenicity in light of this global phylogeography. We propose a strain selection framework, based on robust phylogenetic markers, which will allow for systematic and comprehensive evaluation of new tools for tuberculosis control.

Introduction

It is profoundly disturbing that the means of combating tuberculosis—a disease that kills someone every 16 seconds—are a 100-year-old diagnostic test, a vaccine that was developed 80 years ago, and drugs that have remained fundamentally unchanged for the past 40 years. These facts underlie the call for new tool development outlined in the Global Plan to Stop TB 2006–2015.1 Despite increasing evidence of the importance of strain-to-strain variation in Mycobacterium tuberculosis,2, 3 the implications of this variability on the development of new control tools has been interpreted inconsistently. On the one hand, the prevailing dogma of so-called negligible amounts of sequence variation in this organism compared with other bacteria has lead to the assumption that the comparably low levels of genetic variation in M tuberculosis would have no clinical significance.4, 5 On the other hand, widespread availability of high-resolution genotyping tools has led to a profusion of studies comparing different mycobacterial isolates. In combination with recent advances in mycobacterial genomics and population genetics, these studies have provided novel insights into the biogeography of tuberculosis. There is also increasing evidence that the amount of sequence variation in M tuberculosis might have been underestimated, and that some of this genetic diversity does in fact have important phenotypic consequences. Taken together, this evidence suggests that genotyping methods and a selection process that enable a comprehensive assessment of the genetic variability of M tuberculosis and its consequences are needed for the development of new control tools.

In this Review, we summarise our current understanding of the global phylogeography of M tuberculosis, and propose that it should inform a new, phylogenetically robust framework for strain selection. We review some of the recent findings in pathogenesis and immunology research, with a special focus on strain-specific phenotypic variation. Finally, we discuss ways in which different aspects of the M tuberculosis biology could influence the effectiveness of new tuberculosis control tools.

Section snippets

Differences in virulence

From the first half of the 20th century, numerous studies in guineapigs showed that many M tuberculosis strains isolated from tuberculosis patients in India were less virulent than strains from the UK.6, 7, 8, 9, 10, 11 Following these early studies, animal and macrophage models have been used repeatedly to highlight strain-specific effects on virulence and immunogenicity, providing mounting evidence that genetic variability in M tuberculosis translates into important phenotypic differences.

Appropriate genetic markers

Initial comparative sequencing of M tuberculosis revealed very low sequence diversity compared with other bacteria,4, 5 and population genetic studies showed that this organism exhibits a highly clonal population structure.70, 75, 76 The low levels of sequence variation in M tuberculosis precludes the use of multilocus sequence typing, a standard typing tool successfully applied to many other bacterial pathogens.77, 78 However, recent advances in mycobacterial genomics show that, at the

Geographical structure

In addition to defining a robust phylogeny for M tuberculosis, the results of the five studies reviewed above reveal that the six main strain lineages of M tuberculosis and M africanum are associated with particular geographical regions (figure 2).67, 68, 86, 93 Similar phylogeographical population structures have been reported for other human pathogens,69, 102, 103, 104 some of which have been linked to ancient human migrations.69, 102, 105 In M tuberculosis, more recent historical human

The importance of strain variation for tuberculosis product development

In addition to the increasing evidence from animal and macrophage systems that strain-to-strain variability in M tuberculosis can have important phenotypic consequences, phylogeographical strain variation might affect the development of new diagnostics, drugs, and vaccines.

Concluding remarks

M tuberculosis has a global phylogeographical structure. The molecular markers reviewed here (table) provide the necessary tools to unambiguously classify strains of M tuberculosis within this global phylogenetic framework. The resolution of this classification system will only increase over time as additional sequence data are obtained. This resolution will allow more systematic and comprehensive evaluation of the relevance of strain variability. A large proportion of the global tuberculosis

Search strategy and selection criteria

Data for this Review were identified through searches of Medline and references from relevant articles. Search terms were “Mycobacterium tuberculosis”, “evolution”, “co-evolution” “lineage”, “clade”, “phylogeography”, “virulence”, “immunogenicity”, “phenotype”, “animal model”, and “macrophage”. English language papers were reviewed. No date restrictions were set in these searches.

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