EFFECTS OF AMINOGUANIDINE ON LATENT MURINE TUBERCULOSIS

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.