Unique model of dormant infection for tuberculosis vaccine development.

ABSTRACT

Most individuals exposed to Mycobacterium tuberculosis become infected but hinder the infectious process in dormant foci, known as latent tuberculosis. This limited infection usually stimulates strong T-cell responses, which provide lifelong resistance to tuberculosis. However, latent tuberculosis is still poorly understood, particularly because of the lack of a reliable animal model of dormant infection. Here we show that inoculation of mice with a unique streptomycin-auxotrophic mutant of Mycobacterium tuberculosis recapitulates dormant infection. The mutant grows unimpaired in the presence of streptomycin and no longer grows but remains viable for long periods of time after substrate removal, shifting from the log growth phase to the latent stage, as indicated by augmented production of alpha-crystallin. Mice challenged with the mutant and inoculated with streptomycin for approximately 3 weeks developed a limited infection characterized by a low bacteriological burden and the presence of typical granulomas. After substrate withdrawal, the infection was hindered but few microorganisms remained viable (dormant) in the animals' tissues for at least 6 months. In addition, the animals developed both potent T-cell responses to M. tuberculosis antigens, such as early culture filtrate, Ag85B, and ESAT-6, and resistance to reinfection with virulent M. tuberculosis. Therefore, infection of mice or other animals (e.g., guinea pigs) with M. tuberculosis strain 18b constitutes a simple and attractive animal model for evaluation of antituberculosis vaccines in the context of an M. tuberculosis-presensitized host, a prevailing condition among humans in need of a vaccine.