To catch a killer. What can mycobacterial models teach us about Mycobacterium tuberculosis pathogenesis?

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Mycobacterium tuberculosis is the causative agent of the global tuberculosis epidemic. To combat this successful human pathogen we need a better understanding of the basic biology of mycobacterial pathogenesis. The use of mycobacterial model systems has the potential to greatly facilitate our understanding of how M. tuberculosis causes disease. Recently, studies using mycobacterial models, including M. bovis BCG, M. marinum, and M. smegmatis have significantly contributed to understanding M. tuberculosis. Specifically, there have been advances in genetic manipulation of M. tuberculosis using inducible promoters and recombineering that alleviate technical limitations in working with mycobacteria. Model systems have helped elucidate how secretion systems function at both the molecular level and during virulence. Mycobacterial models have also led to interesting hypotheses about how M. tuberculosis mediates latent infection and host response. While there is utility in using model systems to understand tuberculosis, each of these models represent distinct mycobacterial species with unique environmental adaptations. Directly comparing findings in model mycobacteria to those in M. tuberculosis will illuminate the similarities and differences between these species and increase our understanding of why M. tuberculosis is such a potent human pathogen.

Introduction

The global tuberculosis (TB) epidemic annually accounts for more than 3 million deaths worldwide. Because of the capacity of Mycobacterium tuberculosis to cause latent disease, an estimated 1–2 billion people worldwide are infected with M. tuberculosis. Immunodeficiency caused by malnutrition, old age or HIV infection enhances development of active disease, either from a primary infection or by the reactivation of a latent infection. The global TB epidemic is greatly exacerbated by insufficient public health measures to detect, prevent, and treat TB, and the lengthy antibiotic course required to treat active TB results in nonadherence and development of bacterial resistance. The rising incidence of multi-drug and extremely drug resistant (MDR and XDR) TB is worrisome, indicating that more effort should be directed toward understanding the basic biological pathways that underlie mycobacterial virulence. To this end, mycobacterial model systems have the potential to facilitate our understanding of M. tuberculosis pathogenesis. In this review, we highlight how models have been used over the past two years to study important aspects of M. tuberculosis biology, including virulence factor secretion, dormancy, and host response.

Section snippets

Why are mycobacterial models useful?

The direct study of M. tuberculosis is vital to understanding its pathogenesis. However, use of this pathogen in the laboratory is labor-intensive for several reasons. First, M. tuberculosis is a Category 3 human pathogen, requiring dedicated biosafety level three laboratory and animal facilities, substantial training before handling, and carries with it a risk of accidental exposure [1]. Second, M. tuberculosis grows slowly, doubling every 22 hours in liquid culture. Thus, colony formation

Increasing the genetic tractability of M. tuberculosis using model mycobacteria

The use of M. smegmatis has greatly contributed to genetic tractability of pathogenic mycobacteria, beginning with the advent of plasmids for mycobacterial transformation in the late 80s and early 90s, and the isolation of transformation permissive M. smegmatis strains [3]. Recently, a technique known as ‘recombineering’ was developed for both M. smegmatis and M. tuberculosis, through the exploitation of mycobacteriophage genes that promote recombination from PCR products [4, 5]. Recombineering

Conclusions

Given the dire need to understand the basic biology of mycobacterial pathogenesis, it is important that researchers use all available tools to study M. tuberculosis. We have focused on a small sample of recent studies in which mycobacterial models have significantly contributed to understanding M. tuberculosis. Despite the obvious utility of these models, it is crucial to remember that model organisms such as BCG, M. smegmatis, and M. marinum are themselves unique species that have adapted to

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We would like to thank Dr Matthew Champion and Dr Shaun Lee for the critical reading of this manuscript. MUS is grateful to the National Institutes of Health [grant K08 AI076632] for support.

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