MINIREVIEW Tuberculosis: Latency and Reactivation

Tuberculosis is a major cause of death around the world, with most of the 1.5 million deaths per year attributable to the disease occurring in developing countries. This disease is caused by Mycobacterium tuberculosis, an acid-fast bacillus that is transmitted primarily via the respiratory route. Infection occurs in the lungs, but the organism can seed any organ via hematogenous spread. There are various possible outcomes for a person encountering M. tuberculosis bacilli. First, the bacillus can be immediately destroyed by the host’s innate responses. However, the innate mechanisms that protect against infection are largely uncharacterized; obviously, this is a very important area of study for vaccine development. Second, a proportion of persons infected with M. tuberculosis develops active tuberculosis within a finite time frame (1 to 3 years) (74). This group presumably lacks the ability to both control the initial infection and develop a protective response in time to prevent disease. Finally, it is generally thought that the majority of persons infected with M. tuberculosis have a clinically latent infection; that is, they are infected and purified protein derivative(PPD)positive by skin test but do not present with clinical symptoms and are not contagious to others. However, a number of studies indicate that some infected persons revert to a PPD-negative status, giving weight to the argument that elimination of the organism by the host has occurred (33, 73). In approximately 5 to 10% of latently infected persons, the infection will reactivate and cause active tuberculosis (71). It has been estimated that up to one-third of the world’s population is infected with M. tuberculosis, and this population is an important reservoir for disease reactivation (21). Understanding latent and reactivation tuberculosis, at the level of both the host and the bacillus, is crucial to worldwide control of this disease. Infection with M. tuberculosis is believed to occur in an alveolar macrophage initially. The bacteria replicate within the macrophage and induce cytokines that initiate the inflammatory response in the lungs. Macrophages and lymphocytes migrate to the site of infection and form a granuloma (18). The function of the granuloma is to segregate the infection to prevent spread to the remainder of the lung and to other organs, as well as to concentrate the immune response directly at the site of infection. The granuloma is maintained in a persistently infected host, probably due to chronic stimulation of the immune cells, and forms the basis for a tuberculous lesion. Live bacilli have been isolated from granulomas or tubercles in the lungs of persons with clinically inactive tuberculosis, indicating that the organism can persist in a granulomatous lesion for many years (57, 67). At the most fundamental level, latent tuberculosis can be viewed as an equilibrium between host and bacillus. In response to infection with M. tuberculosis, most persons mount a robust immune response, culminating in the formation of a granulomatous lesion that apparently contains the infection. The host response prevents active disease from occurring, and the bacterium avoids elimination. In most cases, the host response is sufficient to forestall active disease for a lifetime. However, occasionally the immune response fails in some way and the infection reactivates to cause active disease. There are a number of important questions that remain to be answered with respect to latent tuberculosis. How does the host control the initial infection to prevent disease? What immune factors contribute to establishment of a latent infection? Which immunologic components are required to maintain a latent infection and prevent reactivation? How does the bacterium evade host antimcrobial defenses and survive in the face of a strong immune response? Is the bacillus dormant, slowly or intermittently replicating, or metabolically active? All of these questions impact another question relevant to vaccine development: How can the immune system be induced to eliminate, rather than just control, the tubercle bacillus? Otherwise, immune compromise can lead to reactivation of the infection. A clearer picture of the interactions between host and bacillus during latent or persistent infection is essential to answering these questions. The present status of research in these areas is the subject of this review.