Todd Gray

Research Interests

While tuberculosis is perennially a persistent public health threat, and Americans are often shocked to hear that ~1.5 million die of TB annually worldwide. A combination of improved living conditions and the use of antibiotics have effectively reduced its impact in the US. But this situation is tenuous. The ease of international travel assures our continued exposure to this infectious agent. Several complicating factors reduce the efficacy of 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 biology and physiology to learn how to control its growth and pathogenicity. Fortunately, we now have tools that allow us to answer questions that we couldn’t even ask a decade or two ago. We combine innovative next-generation sequencing approaches to identify key processes and interactions that may be next-generation therapeutic targets. Unexpected findings from our studies include the prevalence of leaderless translation initiation and the huge number of small proteins (< 50 amino acids) encoded by mycobacterial genomes, whose functions are completely/mostly unknown.

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. Our conjugation system has also provided initial insights into the original ESX secretion system, ESX-4, including its activation upon cell-cell contact between mating partners. Therefore, our use of DNA transfer as a functional assay of communication in M. smegmatis leverages our experimental system to establish the new field of cell-cell communication in mycobacteria. Identifying communication networks that are active in infecting mycobacterial populations may reveal how disrupting coordinated growth could be a next generation strategy for therapeutics.