To catch a killer. What can mycobacterial models teach us about Mycobacterium tuberculosis pathogenesis?
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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2021, Molecular Aspects of MedicineCitation Excerpt :More recently, it has been shown that Msmeg is susceptible to all tuberculosis drugs in a low-nutrient culture media and proposed Msmeg a suitable model system for preliminary screening of lead molecules for inhibitor design against TB (Lelovic et al., 2020). Further, Msmeg is safer, grows faster and easier genetic tractability to be used as a model system (Li et al., 2004; Sander et al., 2002a,b; Shiloh and Champion, 2010). It has also been claimed that the Msmeg may not be an appropriate model system to fully understand Mtb's physiology (Barry 2001).