Journal
INFECTION AND IMMUNITY
Volume 69, Issue 12, Pages 7711-7717Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/IAI.69.12.7711-7717.2001
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- PHS HHS [R0I 36990] Funding Source: Medline
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Murine macrophages effect potent antimycobacterial function via the production of nitric oxide by the inducible isoform of the enzyme nitric oxide synthase (NOS2). The protective role of reactive nitrogen intermediates (RNI) against Mycobacterium tuberculosis infection has been well established in various murine experimental tuberculosis models using laboratory strains of the tubercle bacillus to establish infection by the intravenous route. However, important questions remain about the in vivo importance of RNI in host defense against AL tuberculosis. There is some evidence that RNI play a lesser role following aerogenic, rather than intravenous, M. tuberculosis Infection of mice. Furthermore, in vitro studies have demonstrated that different strains of Al. tuberculosis, including clinical isolates, vary widely in their susceptibility to the anti mycobacterial effects of RNI. Thus, we sought to test rigorously the protective role of RNI against infection with recent clinical isolates of Al. tuberculosis following both aerogenic and intravenous challenges. Three recently isolated and unique H. tuberculosis strains were used to infect both wild-type (wt) C57BL/6 and NOS2 gene-disrupted mice. Regardless of the route of infection, NOS2(-/-) mice were much more susceptible than wt mice to any of the clinical isolates or to either the Erdman or H37Rv laboratory strain of M. tuberculosis. Mycobacteria replicated to much higher levels in the organs of NOS2(-/-) mice than in those of wt mice. Although the clinical isolates all exhibited enhanced virulence in NOS2(-/-) mice, they displayed distinct growth rates in vivo. The present study has provided results indicating that RNI are required for the control of murine tuberculous infection caused by both laboratory and clinical strains of AL tuberculosis. This protective role of RNI is essential for the control of infection established by either intravenous or aerogenic challenge.
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