Dr. Voskuil joined the Department of Microbiology in March 2003 to work on genes that regulate the dormant state of Mycobacterium tuberculosis during latent infection. M. tuberculosis remains the leading bacterial cause of global mortality. A primary reason for the continued threat from M. tuberculosis lies in its ability to establish an asymptomatic latent infection, which serves as a reservoir for future infections. One-third of the world's population is latently infected with tuberculosis and current treatment of latent infections is inefficient. The low metabolic activity of latent bacilli appears to confer resistance to existing antimicrobials, making global eradication of M. tuberculosis unrealistic.
Little is known about the nature of the latent state in vivo, or the host factors that prevent active disease. Control of bacterial replication in animal models of latency requires a functional immune system including production of IFN-gamma, TNF-alpha and nitric oxide (NO). In vitro studies demonstrate M. tuberculosis has the ability to undergo a distinct physiologic adaptation to a dormant state in response to falling oxygen levels. This hypoxia-induced dormant state is marked by bacteriostasis, in addition to metabolic, chromosomal, and structural changes in the bacteria. Both NO and hypoxia instigate a rapid and dramatic induction of a set of 49 genes (dormancy regulon) in M. tuberculosis. These genes are coordinately regulated and encode functions for adaptation to a dormant state. NO and oxygen levels modulate the induction of the dormancy regulon and concurrently control bacterial respiration and growth. Cytochrome oxidase, the terminal enzyme in electron transport, likely plays a central role as the target of reversible NO respiratory inhibition and the sensor and integrator of NO and oxygen levels. It appears that control of respiration by NO production or oxygen deprivation via granuloma formation is a potent mechanism for immune control of M. tuberculosis. However, the bacilli have evolved mechanisms to survive and persist during the growth arresting state produced by active immune pressure. Research in Dr. Voskuil's laboratory utilizes genetic, microarray, biochemical, and animal studies to investigate the mechanisms employed by M. tuberculosis to survive during long-term latent disease, with a particular focus on the role of the dormancy regulon.