Approximately one third of the world’s population is infected with Mycobacterium tuberculosis, and there are roughly 2 million tuberculosis-related deaths annually. Treatment for tuberculosis infection is complicated by long courses of antibiotics and the recent emergence of strains resistant to first and second line defenses. The biology of mycobacterial infection is complex, and poorly understood.
During infection, the pathogen manipulates the host cell to avoid detection by the immune response, and to create a niche that favors replication and persistence. One of the major virulence determinants used by mycobacterial and many Gram-positive pathogens is the ESX-1 (ESAT-6 System-1) export system. While there are many proteins known to play a role in ESX-1 protein secretion, the way the majority of these proteins function is unclear.
We are interested in 1) identifying novel components and substrates of the ESX-1 system, 2) determining how components of this complex secretion machine function to select and transport protein substrates during infection. To do so, we use both Mycobacterium marinum, a mycobacterial species closely related to Mycobacterium tuberculosis and M. tuberculosis itself. M. marinum causes a tuberculosis-like infection in ectotherms, but rarely causes serious disease in humans. The ESX-1 secretion system is conserved and functional in M. marinum, and strains lacking the secretion machine are severely attenuated. This attenuation can be complemented using the paralogous genes from M. tuberculosis, suggesting that the functions of these proteins are conserved in both species.
Additional studies are ongoing to understand the interaction of M. marinum with the environmental amoeba, Acanthamoeba castellanii. We use this host-pathogen model to study the ESX-1 secretion system, and to identify mycobacterial virulence determinants.
We use molecular, genetic, proteomic and biochemical approaches to better understand mycobacterial pathogenesis. Understanding how mycobacteria cause disease will lead to better anti-tuberculosis vaccine development.