A unique feature of Mycobacterium tuberculosis is its ability to estab
lish latent infection in the human host, which can reactivate to claus
e disease years later. In the present study, the mechanisms involved i
n the control of latent tuberculous infection were examined using two
murine experimental tuberculosis models. Analysis of the model involvi
ng infection of mice with a relatively low inoculum of the virulent Er
dman strain of M. tuberculosis indicated that in vivo inhibition of re
active nitrogen intermediate (RNI) production by the nitric oxide synt
hase inhibitor aminoguanidine resulted in reactivation. This reactivat
ion was evidenced by hepatosplenomegaly, a robust tissue granulomatous
reaction, and increased bacillary load, IFN-gamma, TNF-alpha, and ind
ucible nitric oxide synthase were all expressed throughout the latent
phase of infection, Reactivation of latent tuberculous infection by am
inoguanidine treatment was confirmed using a second murine tuberculosi
s model based on treatment with antimycobacterial drugs. Results obtai
ned using this drug-based model also suggested the existence of an RNI
-independent antimycobacterial mechanism(s) operative in the latent ph
ase of infection, Together, these data suggest that both RNI-dependent
and -independent mechanisms contribute to the prevention of tuberculo
us reactivation.