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Todd Gray, Ph.D.
Tuberculosis occupies the top spot as the world’s number one infectious killer. A combination of improved living conditions and the use of antibiotics have reduced the domestic incidence of tuberculosis so effectively that it has nearly vanished from the US.
But this situation is tenuous. Americans are often shocked to hear that one-third of global population is infected with Mycobacterium tuberculosis. The ease of international travel assures our continued exposure to this infectious agent. Several complicating factors reduce the efficacy the antibiotic regimens used to treat tuberculosis, ultimately promoting drug resistance. The emergence of escalating levels of antibiotic resistant (multi-, extremely-, and totally-drug resistant) strains of M. tuberculosis pose major public health threats wherever they are found.
New strategies to fight tuberculosis are required. To this end, we must better understand M. tuberculosis to better learn how to control its growth and pathogenicity. Fortunately, we now have tools that allow us to answer questions that we couldn’t even a decade or two ago. We combine multiple genome-wide tools, such as whole-genome sequencing, expression arrays, and ChIP-chip assays to identify key processes and interactions that may be exploited as therapeutic targets.
Since many of the M. tuberculosis genes, proteins, and biological pathways are conserved in other mycobacteria, we use the fast-growing, non-pathogenic Mycobacterium smegmatis for most of our studies. We have described a novel form of conjugal DNA transfer between strains of M. smegmatis, and found that it relies on the activity of the same secretory apparatus (ESX-1) that is required for pathogenicity in M. tuberculosis. We consistently demonstrate the interchangeability of ESX-1 components between these mycobacterial species by cross complementation of multiple esx1 genes. Therefore, our use of DNA transfer as a functional ESX-1 assay in M. smegmatis is an effective proxy for ESX-1 function, and therefore ESX-1 pathogenicity, in M. tuberculosis. We expect that further leveraging our experimental system will expedite the development of the needed next generation of tuberculosis vaccines or therapeutics.