The Journal of Experimental Medicine
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Published 7 October 2002. doi:10.1084/jem.20021186
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© Rockefeller University Press, 0022-1007/2002/10/991/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 7, October 7, 2002 991-998

Virulent but not Avirulent Mycobacterium tuberculosis Can Evade the Growth Inhibitory Action of a T Helper 1–dependent, Nitric Oxide Synthase 2–independent Defense in Mice

Yu-Jin Jung, Ronald LaCourse, Lynn Ryan and Robert J. North

The Trudeau Institute, Saranac Lake, NY 12983

Address correspondence to Robert J. North, The Trudeau Institute, 100 Algonquin Ave., PO Box 59, Saranac Lake, NY 12983. Phone: 518-891-3080; Fax: 518-891-5126; E-mail: rjnorth{at}northnet.org

Control of infection with virulent Mycobacterium tuberculosis (Mtb) in mice is dependent on the generation of T helper (Th)1-mediated immunity that serves, via secretion of interferon (IFN)-{gamma} and other cytokines, to upregulate the antimycobacterial function of macrophages of which the synthesis of inducible nitric oxide synthase (NOS)2 is an essential event. As a means to understanding the basis of Mtb virulence, the ability of gene-deleted mice incapable of making NOS2 (NOS2-/-), gp91Phox subunit of the respiratory burst NADPH-oxidase complex (Phox-/-), or either enzyme (NOS2/Phox-/-), to control airborne infection with the avirulent R1Rv and H37Ra strains of Mtb was compared with their ability control infection with the virulent H37Rv strain. NOS2-/-, Phox-/-, and NOS2/Phox-/- mice showed no deficiency in ability to control infection with either strain of avirulent Mtb. By contrast, NOS2-/- mice, but not Phox-/- mice, were incapable of controlling H37Rv infection and died early from neutrophil-dominated lung pathology. Control of infection with avirulent, as well as virulent Mtb, depended on the synthesis of IFN-{gamma}, and was associated with a substantial increase in the synthesis in the lungs of mRNA for IFN-{gamma} and NOS2, and with production of NOS2 by macrophages at sites of infection. The results indicate that virulent, but not avirulent, Mtb can overcome the growth inhibitory action of a Th1–dependent, NOS2-independent mechanism of defense.

Key Words: M. tuberculosis • virulence • NOS2 synthase • NADPH-oxidase • Th1 immunity


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