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Infection and Immunity, December 2001, p. 7711-7717, Vol. 69, No. 12
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.12.7711-7717.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

The Inducible Nitric Oxide Synthase Locus Confers Protection against Aerogenic Challenge of Both Clinical and Laboratory Strains of Mycobacterium tuberculosis in Mice

Charles A. Scanga,1,dagger Vellore P. Mohan,2,3 Kathryn Tanaka,4 David Alland,2,3 JoAnne L. Flynn,1,5 and John Chan2,3,*

Departments of Molecular Genetics and Biochemistry1 and Medicine,5 University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, and Departments of Medicine,2 Microbiology and Immunology,3 and Pathology,4 Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York 10461

Received 11 April 2001/Returned for modification 28 May 2001/Accepted 20 July 2001

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 M. 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 M. 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 of M. tuberculosis following both aerogenic and intravenous challenges. Three recently isolated and unique M. 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 M. tuberculosis. This protective role of RNI is essential for the control of infection established by either intravenous or aerogenic challenge.

* Corresponding author. Mailing address: Departments of Medicine, Microbiology, and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Phone: (718) 430-2678. Fax: (718) 430-8968. E-mail: jchan{at}aecom.yu.edu.

dagger Present address: Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.

Infection and Immunity, December 2001, p. 7711-7717, Vol. 69, No. 12
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.12.7711-7717.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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