Expression of the nitric oxide synthase 2 gene is not essential for early control of Mycobacterium tuberculosis in the murine lung.
The interleukin-12 and gamma interferon (IFN-gamma) pathway of macrophage activation plays a pivotal role in controlling tuberculosis. In the murine model, the generation of supplementary nitric oxide by the induction of the nitric oxide synthase 2 (NOS2) gene product is considered the principal antimicrobial mechanism of IFN-gamma-activated macrophages. Using a low-dose aerosol-mediated infection model in the mouse, we have investigated the role of nitric oxide in controlling Mycobacterium tuberculosis in the lung. In contrast to the consequences of a systemic infection, a low dose of bacteria introduced directly into the lungs of mice lacking the NOS2 gene is controlled almost as well as in intact animals. This is in contrast to the rapid progression of disease in mice lacking IFN-gamma or a key member of the IFN signaling pathway, interferon regulatory factor 1. Thus while IFN-gamma is pivotal in early control of bacterial growth in the lung, this control does not completely depend upon the expression of the NOS2 gene. The absence of inducible nitric oxide in the lung does, however, result in increased polymorphonuclear cell involvement and eventual necrosis in the pulmonary granulomas of the infected mice lacking the NOS2 gene.
Cooper
A M
AM
Mycobacterial Research Laboratories, Department of Microbiology, Colorado State University, Fort Collins, Colorado 80523, USA. acooper@cvmbs.colostate.edu
Pearl
J E
JE
Brooks
J V
JV
Ehlers
S
S
Orme
I M
IM
D000818:Animals; D004268:DNA-Binding Proteins / Q000502:physiology; D006099:Granuloma / Q000209:etiology; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000502:physiology; D008168:Lung / Q000382:microbiology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000254:growth & development*; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II; D010750:Phosphoproteins / Q000502:physiology; D014397:Tuberculosis, Pulmonary / Q000209:etiology
D004268:DNA-Binding Proteins; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D010750:Phosphoproteins; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse