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 that have potent antimicrobial activity. Resistance to killing by macrophages is critical to the virulence of Mycobacterium tuberculosis. M. tuberculosis has two genes encoding superoxide dismutase proteins, sodA and sodC. SodC is a Cu,Zn superoxide dismutase responsible for only a minor portion of the superoxide dismutase activity of M. tuberculosis. However, SodC has a lipoprotein binding motif, which suggests that it may be anchored in the membrane to protect M. tuberculosis from reactive oxygen intermediates at the bacterial 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. In this report, we show that the M. tuberculosis sodC mutant is readily killed by superoxide generated externally, while the isogenic parental M. tuberculosis is unaffected under these conditions. Furthermore, the sodC mutant has enhanced susceptibility to killing by gamma interferon (IFN-gamma)-activated murine peritoneal macrophages producing oxidative burst products but is unaffected by macrophages not activated by IFN-gamma or by macrophages from respiratory burst-deficient mice. These observations establish that the Cu,Zn superoxide dismutase contributes to the resistance of M. tuberculosis against oxidative burst products generated by activated macrophages.
Piddington
D L
DL
Department of Pathology, University of California, San Diego, La Jolla, California 92093-0640, USA.
Fang
F C
FC
Laessig
T
T
Cooper
A M
AM
Orme
I M
IM
Buchmeier
N A
NA
D000818:Animals; D002478:Cells, Cultured; D003300:Copper; D029968:Escherichia coli Proteins; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000382:microbiology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016296:Mutagenesis; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics; D009569:Nitric Oxide / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000502:physiology; D052248:Nitric Oxide Synthase Type I; D016897:Respiratory Burst; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013481:Superoxides / Q000494:pharmacology*; D015032:Zinc
D029968:Escherichia coli Proteins; D008562:Membrane Glycoproteins; D013481:Superoxides; D009569:Nitric Oxide; D003300:Copper; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D013482:Superoxide Dismutase; C116114:sodC protein, E coli; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D015032:Zinc