The inducible nitric oxide synthase locus confers protection against aerogenic challenge of both clinical and laboratory strains of Mycobacterium tuberculosis in mice

Murine macrophages effect potent antimycobacterial function via the product ion of nitric oxide by the inducible isoform of the enzyme nitric oxide syn thase (NOS2). The protective role of reactive nitrogen intermediates (RNI) against Mycobacterium tuberculosis infection has been well established in v arious murine experimental tuberculosis models using laboratory strains of the tubercle bacillus to establish infection by the intravenous route. Howe ver, important questions remain about the in vivo importance of RNI in host defense against AL tuberculosis. There is some evidence that RNI play a le sser role following aerogenic, rather than intravenous, M. tuberculosis Inf ection of mice. Furthermore, in vitro studies have demonstrated that differ ent strains of Al. tuberculosis, including clinical isolates, vary widely i n their susceptibility to the anti mycobacterial effects of RNI. Thus, we s ought to test rigorously the protective role of RNI against infection with recent clinical isolates of Al. tuberculosis following both aerogenic and i ntravenous challenges. Three recently isolated and unique H. tuberculosis s trains were used to infect both wild-type (wt) C57BL/6 and NOS2 gene-disrup ted mice. Regardless of the route of infection, NOS2(-/-) mice were much mo re susceptible than wt mice to any of the clinical isolates or to either th e Erdman or H37Rv laboratory strain of M. tuberculosis. Mycobacteria replic ated to much higher levels in the organs of NOS2(-/-) mice than in those of wt mice. Although the clinical isolates all exhibited enhanced virulence i n NOS2(-/-) mice, they displayed distinct growth rates in vivo. The present study has provided results indicating that RNI are required for the contro l of murine tuberculous infection caused by both laboratory and clinical st rains of AL tuberculosis. This protective role of RNI is essential for the control of infection established by either intravenous or aerogenic challen ge.