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Drug Tolerance | Metabolism | Immune Evasion | Persistence | Microfluidics

"Following infection, the incubation period of tuberculosis ranges from a few weeks to a lifetime." This remark from a leading epidemiologist encapsulates the chief mystery and challenge of tuberculosis (TB): the ability of the pathogen to persist in the tissues indefinitely in the face of the host-immune response. Although in most cases infection is effectively contained by host immunity, failure to eliminate the “enemy within” means that TB can flare up again if the immune system is weakened. Nearly 2 billion individuals worldwide, including 10 to 15 million in the United States alone, are asymptomatically infected with Mycobacterium tuberculosis. Over the course of a lifetime, 100 to 200 million of these latent infections will reactivate and develop into full-blown TB — an enormous burden of future disease arising from infections that are already established. At present, virtually nothing is being done to reduce this vast and pervasive reservoir of contagion because effective and practicable tools are lacking. In recognition of this unmet need, the National Academy of Sciences’ Institute of Medicine in a recent report stressed that “the first priority for research is development of an understanding of latent infection.”

What are the immune mechanisms that maintain TB latency and block reactivation? Why is infection contained but not eradicated? What is the physiologic state of persistent mycobacteria? What are the mechanisms that defend the pathogen against the onslaught of host immunity? We are taking a molecular-genetic approach to address these unanswered questions in TB. Our studies exploit recent technological advances that permit the direct analysis of M. tuberculosis in its natural environment, the mammalian lung. A long-term goal of our research is the development of new and more effective strategies for TB control. With 10 million new cases and 2 to 3 million deaths each year attributed to TB, the need could hardly be greater.