Mycobacterium tuberculosis residing within pulmonary granulomas and cavities 
represents an important reservoir of persistent organisms during human latent 
tuberculosis infection. We present a novel in vivo model of tuberculosis 
involving the encapsulation of bacilli in semidiffusible hollow fibers that are 
implanted subcutaneously into mice. Granulomatous lesions develop around these 
hollow fibers, and in this microenvironment, the organisms demonstrate an 
altered physiologic state characterized by stationary-state colony-forming unit 
counts and decreased metabolic activity. Moreover, these organisms show an 
antimicrobial susceptibility pattern similar to persistent bacilli in current 
models of tuberculosis chemotherapy in that they are more susceptible to the 
sterilizing drug, rifampin, than to the bactericidal drug isoniazid. We used 
this model of extracellular persistence within host granulomas to study both 
gene expression patterns and mutant survival patterns. Our results demonstrate 
induction of dosR (Rv3133c) and 20 other members of the DosR regulon believed to 
mediate the transition into dormancy, and that rel(Mtb) is required for 
Mycobacterium tuberculosis survival during extracellular persistence within host 
granulomas. Interestingly, the dormancy phenotype of extracellular M. 
tuberculosis within host granulomas appears to be immune mediated and 
interferon-gamma dependent.