Mycobacterial infections
Does M. tuberculosis genomic diversity explain disease diversity?

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The outcome of tuberculosis infection and disease is highly variable. This variation has been attributed primarily to host and environmental factors, but better understanding of the global genomic diversity in the Mycobacterium tuberculosis complex (MTBC) suggests that bacterial factors could also be involved. Review of nearly 100 published reports shows that MTBC strains differ in their virulence and immunogenicity in experimental models, but whether this phenotypic variation plays a role in human disease remains unclear. Given the complex interactions between the host, the pathogen and the environment, linking MTBC genotypic diversity to experimental and clinical phenotypes requires an integrated systems epidemiology approach embedded in a robust evolutionary framework.

Introduction

The impact of strain variation for human disease has been well established for several bacterial pathogens. In Escherichia coli, Neisseria menigitidis, Haemophylus influenzae, Bordetella and Streptococcus species, some strains are more likely to cause invasive disease and others are emerging as a consequence of vaccine escape [1, 2, 3, 4, 5, 6, 7, 8]. In the Mycobacterium tuberculosis complex (MTBC), a possible role for strain diversity in human tuberculosis (TB) is increasingly being suggested from work in various infection models (reviewed in [9, 10, 11, 12, 13]). But if and how MTBC genomic diversity influences human disease in clinical settings remain open questions. Starting in the first half of the 20th century, studies in guinea-pigs and mice reported differences in virulence among strains of tubercle bacilli [14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24]. However, until the development of the first molecular strain-typing techniques in the early 1990s, there was a general belief that genetic diversity within MTBC was too limited to account for these differences in virulence. The highly variable outcomes in TB, which ranges from lifelong asymptomatic infection to severe extrapulmonary disease affecting multiple organs were primarily attributed to host and environmental factors [25]. Moreover, most of the pathogenesis research on TB has concentrated on the laboratory strains H37Rv and Erdman, with little attention to clinical strains. More recently however, there has been mounting interest on studying clinical isolates, partially because of the realization that results from laboratory strains can suffer from artefacts because of bacterial adaptation to the laboratory [26, 27].

One additional difficulty in trying to link genomic diversity to phenotypic diversity in MTBC has been the lack of appropriate tools to index genomic diversity and classify strains. MTBC is a genetically monomorphic organism and some of the genotyping tools applied to other bacterial pathogens are uninformative in MTBC [28, 29]. Here we start by reviewing the genotyping methods currently used in MTBC with a particular focus on their limitations. We then review the current evidence for strain phenotypic variation in MTBC from experimental and clinical studies.

Section snippets

Measuring genetic diversity in MTBC – review of past and current tools

In the early 1990s, IS6110 RFLP was established as the first gold standard for fine typing of MTBC. During the following years, molecular epidemiological studies generated important new insights into the dynamics of transmission, relapse, and re-infection in TB [30, 31]. At the same time, as large international collections of MTBC strains began to accumulate, IS6110 RFLP analysis of these strain collections identified the first genotype ‘families’ among MTBC. These studies also highlighted that

A phylogenetic framework for strain classification

Although DNA sequence data allow inferring robust phylogenetic structures, delineating biologically meaningful groupings within a continuous spectrum of genotypic diversity is not easy, and to some extent arbitrary. Nevertheless, defining such boundaries within species is important for the purpose of strain classification. The difficulty of determining biologically meaningful groupings within related bacteria arises at multiple taxonomic levels. For example, there is still no widely accepted

Experimental evidence for phenotypic strain diversity

To date at least 67 studies have explored strain-specific phenotypic differences in vitro or in animal models of infection (Table 1). The most commonly studied strains are laboratory or reference strains, but 38 of these studies have also included clinical isolates.

Clinical evidence of phenotypic strain diversity

To understand the impact of MTBC genotype on TB in humans it is necessary to link findings from experimental studies to human infections. We identified a total of 33 studies that have investigated the effect of MTBC genetic diversity on clinical outcome (Table 2). Significant differences among MTBC lineages have been reported in terms of their propensity to cause secondary cases in different human population [37], their progression to active disease in recently exposed household contacts [69],

Molecular mechanisms

To determine if and how strain genetic diversity in MTBC affects TB infection and disease, we also will need to understand the molecular mechanisms leading from strain genotype to the various experimental and clinical phenotypes. To date, only a few reports have explored the underlying mechanisms responsible for phenotypic differences observed in experimental studies. Reed et al. [51] reported that the hypoinflammatory and hypervirulence phenotype of strain HN878 was linked to the production of

More data are needed

After reviewing nearly 100 papers, the only clear message coming out of these studies is that MTBC strains differ in their virulence, immunogenicity and susceptibility to oxidative stress in infection models. However, human studies in clinical settings have largely failed to detect common patterns in the effect of strain variation on outcome of TB. The inconsistencies in clinical studies could be due to many factors, including host and environmental factors like the nature and quality of the TB

From genome sequencing to systems epidemiology

TB infection and disease result from a complex interaction between the pathogen, the host and the environment [25]. TB pathogenesis is not driven by individual virulence factors but through a complex process involving many bacterial factors which interact with many components of the host immune system. Hence to understand TB, an integrative approach is needed, taking into account the many interactions between the host and pathogen factors.

Although many reports have studied human genetic

Concluding remarks

There is now clear evidence that different strains of MTBC differ in virulence and immunogenicity in experimental infection models. However, if and how these differences impact on human disease remains unclear. Studies of the effect of MTBC strain diversity in clinical settings have failed to find any consistent patterns. Hence at this stage, we would answer the question as to whether MTBC diversity matters for TB in humans with a cautious ‘maybe’. Clearly, more data are needed. It is also

Acknowledgements

We thank Sonia Borrell for help and comments on the manuscript. MC is supported by a fellowship from Programa VALi+d per a investigadors en fase postdoctoral de la Comunitat Valenciana. The work in our laboratory is supported by the Swiss National Science Foundation, the Medical Research Council, UK, the Leverhulme-Royal Society Africa Award AA080019, and the USA National Institutes of Health grants HHSN266200700022C, AI034238 and AI090928.

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