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

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)-γ 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(−/−)), gp91(Phox) 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-γ, and was associated with a substantial increase in the synthesis in the lungs of mRNA for IFN-γ 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.