INHIBITION OF VIRULENT MYCOBACTERIUM-TUBERCULOSIS BY BCG(R) AND BCG(S) MACROPHAGES CORRELATES WITH NITRIC-OXIDE PRODUCTION

The Nramp1 gene controls macrophage resistance or susceptibility to se veral intracellular microorganisms; however, there is conflicting evid ence regarding its role during infection with virulent Mycobacterium t uberculosis. Nitric oxide (NO) is a potent antimycobacterial agent pro duced by macrophages, which is also regulated by Nramp1. The in vitro ability of B10R (resistant) and B10S (susceptible) murine macrophages to inhibit M. tuberculosis H37Rv and to produce NO in response to infe ction and interferon-gamma (IFN-gamma) was compared. Infected B10R mac rophages inhibited [H-3]uracil incorporation by ill, tuberculosis and produced higher amounts of NO than did BIOS macrophages. IFN-gamma inc reased the inhibitory activity of both cells. Inhibition of M. tubercu losis by IFN-gamma-activated B10R macrophages was reversed by N-G-mono methyl-L-arginine (N(G)MMA). L-arginine restored NO production and inc reased the antimycobacterial activity by IFN-gamma-stimulated N(G)MMA- treated macrophages. The Bcg/Nramp1 gene may regulate macrophage resis tance or susceptibility to virulent M. tuberculosis by a differential capability of these cells to produce NO.