Cu,Zn Superoxide Dismutase ofMycobacterium tuberculosisContributes to Survival in Activated Macrophages That Are Generating an Oxidative Burst

Abstract

Macrophages produce reactive oxygen species and reactive nitrogen species that have potent antimicrobial activity. Resistance to killing by macrophages is critical to the virulence ofMycobacterium tuberculosis. M. tuberculosishas two genes encoding superoxide dismutase proteins,sodAandsodC. SodC is a Cu,Zn superoxide dismutase responsible for only a minor portion of the superoxide dismutase activity ofM. tuberculosis. However, SodC has a lipoprotein binding motif, which suggests that it may be anchored in the membrane to protectM. tuberculosisfrom reactive oxygen intermediates at the bacterial surface. To examine the role of the Cu,Zn superoxide dismutase in protectingM. tuberculosisfrom the toxic effects of exogenously generated reactive oxygen species, we constructed a null mutation in thesodCgene. In this report, we show that theM. tuberculosis sodCmutant is readily killed by superoxide generated externally, while the isogenic parentalM. tuberculosisis unaffected under these conditions. Furthermore, thesodCmutant has enhanced susceptibility to killing by gamma interferon (IFN-γ)-activated murine peritoneal macrophages producing oxidative burst products but is unaffected by macrophages not activated by IFN-γ or by macrophages from respiratory burst-deficient mice. These observations establish that the Cu,Zn superoxide dismutase contributes to the resistance ofM. tuberculosisagainst oxidative burst products generated by activated macrophages.