The silent plague: Regulation of latent tuberculosis infections

Nearly one-third of the world's population carries viable tubercle bacilli in their bodies but do not display disease. This represents the clinical definition of a latently infected patient who can reactivate and produce active disease at any time. Despite a great deal of investigation, it remains unclear exactly where or what state the bacteria responsible, Mycobacterium tuberculosis, are in during this latent phase of infection and how they enter and leave dormancy. Neither the exact signals nor the complete regulatory pathways involved are fully understood. This review is not meant to be a comprehensive overview of tuberculosis latency, but is meant to briefly raise some of the more critical and controversial issues in the literature related to latent infections, focusing primarily on bacterial gene expression and offering suggestions for directions of future research. We conclude that there are several signals involved in establishment of the persistent state during latent infections and reactivation from that state that remain to be elucidated. Interestingly, the clinical definition of latency is not likely to be due to bacteria in the same state in all patients. The complexity of these events offers opportunities to combat tuberculosis through manipulation of the bacterial persistent state and the interacting host immune response. Exploitation of bacterial persistence during latent infections as well as the signals that control these events may be critical to the ultimate goal of eradicating this ongoing plague of mankind.