Cu,Zn superoxide dismutase of Mycobacterium tuberculosis contributes to survival in activated macrophages that are generating an oxidative burst

Macrophages produce reactive oxygen species and reactive nitrogen species t hat have potent antimicrobial activity. Resistance to killing by macrophage s is critical to the virulence of Mycobacterium tuberculosis. M. tuberculos is has two genes encoding superoxide dismutase proteins, sodA and sodC. Sod C is a Cu,Zn superoxide dismutase responsible for only a minor portion of t he superoxide dismutase activity of M. tuberculosis. However, SodC has a li poprotein binding motif, which suggests that it may be anchored in the memb rane to protect M. tuberculosis from reactive oxygen intermediates at the b acterial surface. To examine the role of the Cu,Zn superoxide dismutase in protecting M. tuberculosis from the toxic effects of exogenously generated reactive oxygen species, we constructed a null mutation in the sodC gene. I n this report, we show that the M. tuberculosis sodC mutant is readily kill ed by superoxide generated externally, while the isogenic parental M. tuber culosis is unaffected under these conditions. Furthermore, the sodC mutant has enhanced susceptibility to killing by gamma interferon (IFN-gamma)-acti vated murine peritoneal macrophages producing oxidative burst products but is unaffected by macrophages not activated by IFN-gamma or by macrophages f rom respiratory burst-deficient mice. These observations establish that the Cu,Zn superoxide dismutase contributes to the resistance of M. tuberculosi s against oxidative burst products generated by activated macrophages.