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. 2005 Oct;73(10):6562-6.
doi: 10.1128/IAI.73.10.6562-6566.2005.

Role of NADase in virulence in experimental invasive group A streptococcal infection

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Role of NADase in virulence in experimental invasive group A streptococcal infection

Angela L Bricker et al. Infect Immun. 2005 Oct.

Abstract

Group A streptococci (GAS) produce several exoproteins that are thought to contribute to the pathogenesis of human infection. Two such proteins, streptolysin O (SLO) and NAD(+)-glycohydrolase (NADase), have been shown to interact functionally as a compound signaling toxin. When GAS are bound to the surface of epithelial cells in vitro, SLO forms pores in the cell membrane and delivers NADase to the epithelial cell cytoplasm. In vitro, intoxication of keratinocytes with NADase is associated with cytotoxic effects and induction of apoptosis; however, the importance of NADase during infection of an animal host has not been established. We employed isogenic GAS mutants to assess the contribution of NADase activity to GAS virulence in vivo using mouse models of invasive soft-tissue infection and septicemia. In both models, mutant GAS that lacked NADase activity were significantly attenuated for virulence compared with the isogenic wild-type parent, confirming an important role for NADase in the infection of a host animal. A double mutant lacking SLO and NADase activity had an intermediate virulence phenotype, consistent with the hypothesis that SLO evokes a protective innate immune response. We conclude that NADase and SLO together enhance GAS virulence in vivo.

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Figures

FIG. 1.
FIG. 1.
Effect of inactivating NADase on local tissue necrosis after subcutaneous inoculation with GAS. Each data point represents the area of skin necrosis surrounding the inoculation site on the indicated day after subcutaneous inoculation with GAS strain 771nga−slo+ (A) or GAS wild-type strain 771nga+slo+ (B). Mean lesion size is indicated by a cross. Data are from four independent experiments and a total of 40 mice for each challenge strain. P = 0.001 for comparison between strains.
FIG. 2.
FIG. 2.
Effect of inactivating both NADase and SLO on local tissue necrosis after subcutaneous inoculation with GAS. Each data point represents the area of skin necrosis surrounding the inoculation site on the indicated day after subcutaneous inoculation with GAS strain 771nga−slo− (A) or GAS wild-type strain 771nga+slo+ (B). Mean lesion size is indicated by a cross. Data are from two independent experiments and a total of 20 mice for each challenge strain. P values were not significant for comparison between strains.
FIG. 3.
FIG. 3.
Cumulative bacteremia after subcutaneous inoculation with wild-type or mutant strains of GAS. Each data point represents the percentage of mice with at least one positive blood culture as of the indicated day. (A) Mice were challenged with GAS strain 771nga−slo+ (squares) or wild-type GAS strain 771nga+slo+ (circles); data are from four independent experiments and a total of 40 mice for each challenge strain. P < 0.01 for comparison between strains. (B) Mice were challenged with GAS strain 771nga−slo− (diamonds) or wild-type GAS strain 771nga+slo+ (circles); data are from two independent experiments and a total of 20 mice for each challenge strain. P values were not significant for comparison between strains.
FIG. 4.
FIG. 4.
Survival after subcutaneous inoculation with wild-type or mutant strains of GAS. (A) Mice challenged with GAS strain 771nga−slo+ (squares) or wild-type GAS strain 771nga+slo+ (circles); data are from four independent experiments and a total of 40 mice for each challenge strain. P = 0.04 for comparison between strains. (B) Mice challenged with GAS strain 771nga−slo− (diamonds) or wild-type GAS strain 771nga+slo+ (circles); data are from two independent experiments and a total of 20 mice for each challenge strain. P = 0.04 for comparison between strains.
FIG. 5.
FIG. 5.
Survival after intraperitoneal inoculation with wild-type or mutant strains of GAS. Mice were challenged with GAS strain 771nga−slo+ (squares), 771nga−slo− (diamonds), or wild-type strain 771nga+slo+ (circles). Data are from 30 to 36 mice for each challenge strain. Survival was significantly greater in animals challenged with 771nga−slo+ (P < 0.001) or 771nga−slo− (P = 0.003) compared to 771nga+slo+.

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