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)-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(-/-)), 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-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.
Jung
Yu-Jin
YJ
The Trudeau Institute, Saranac Lake, NY 12983, USA.
LaCourse
Ronald
R
Ryan
Lynn
L
North
Robert J
RJ
D000818:Animals; D002455:Cell Division; D003433:Crosses, Genetic; D008099:Liver / Q000382:microbiology / Q000473:pathology; D008168:Lung / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009169:Mycobacterium tuberculosis / Q000254:growth & development / Q000276:immunology* / Q000472:pathogenicity*; D019001:Nitric Oxide Synthase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D013154:Spleen / Q000382:microbiology / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology*; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000473:pathology; D014774:Virulence / Q000276:immunology
D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse