The Inducible Nitric Oxide Synthase Locus Confers Protection against Aerogenic Challenge of Both Clinical and Laboratory Strains ofMycobacterium tuberculosisin Mice
- 1 December 2001
- journal article
- Published by American Society for Microbiology in Infection and Immunity
- Vol. 69 (12), 7711-7
- https://doi.org/10.1128/iai.69.12.7711-7717.2001
Abstract
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) againstMycobacterium tuberculosisinfection 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 againstM. tuberculosis. There is some evidence that RNI play a lesser role following aerogenic, rather than intravenous,M. tuberculosisinfection of mice. Furthermore, in vitro studies have demonstrated that different strains ofM. tuberculosis, including clinical isolates, vary widely in their susceptibility to the antimycobacterial effects of RNI. Thus, we sought to test rigorously the protective role of RNI against infection with recent clinical isolates ofM. tuberculosisfollowing both aerogenic and intravenous challenges. Three recently isolated and uniqueM. tuberculosisstrains were used to infect both wild-type (wt) C57BL/6 andNOS2gene-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 ofM. 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 ofM. tuberculosis. This protective role of RNI is essential for the control of infection established by either intravenous or aerogenic challenge.Keywords
This publication has 33 references indexed in Scilit:
- Fate ofMycobacterium tuberculosiswithin Murine Dendritic CellsInfection and Immunity, 2001
- Expression of the Nitric Oxide Synthase 2 Gene Is Not Essential for Early Control ofMycobacterium tuberculosisin the Murine LungInfection and Immunity, 2000
- Toxicity of nitrogen oxides and related oxidants on mycobacteria: M. tuberculosis is resistant to peroxynitrite anionTubercle and Lung Disease, 1999
- Enhanced Capacity of a Widespread Strain ofMycobacterium tuberculosisto Grow in Human MacrophagesThe Journal of Infectious Diseases, 1999
- Induction of Nitric Oxide in Human Monocytes and Monocyte Cell Lines byMycobacterium tuberculosisNitric Oxide, 1998
- Mycobacterium tuberculosis (MTB)- stimulated production of nitric oxide by human alveolar macrophages and relationship of nitric oxide production to growth inhibition of MTBTubercle and Lung Disease, 1997
- Inducible nitric oxide synthase in pulmonary alveolar macrophages from patients with tuberculosis.The Journal of Experimental Medicine, 1996
- Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthaseCell, 1995
- Transmission of Tuberculosis in New York City -- An Analysis by DNA Fingerprinting and Conventional Epidemiologic MethodsNew England Journal of Medicine, 1994
- Mycobacterial virulence. Virulent strains of Mycobacteria tuberculosis have faster in vivo doubling times and are better equipped to resist growth-inhibiting functions of macrophages in the presence and absence of specific immunity.The Journal of Experimental Medicine, 1993