Bricker Angela L, Carey Vincent J, Wessels Michael R
Channing Laboratory, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Infect Immun. 2005 Oct;73(10):6562-6. doi: 10.1128/IAI.73.10.6562-6566.2005.
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.
A组链球菌（GAS）产生多种外蛋白，这些外蛋白被认为与人类感染的发病机制有关。其中两种蛋白，链球菌溶血素O（SLO）和NAD⁺-糖水解酶（NADase），已被证明作为一种复合信号毒素在功能上相互作用。当GAS在体外与上皮细胞表面结合时，SLO在细胞膜上形成孔道，并将NADase递送至上皮细胞胞质中。在体外，角质形成细胞被NADase中毒与细胞毒性作用和凋亡诱导有关；然而，NADase在动物宿主感染过程中的重要性尚未确定。我们使用同基因GAS突变体，通过侵袭性软组织感染和败血症的小鼠模型来评估NADase活性对GAS体内毒力的贡献。在这两种模型中，与同基因野生型亲本相比，缺乏NADase活性的突变体GAS的毒力显著减弱，证实了NADase在宿主动物感染中的重要作用。缺乏SLO和NADase活性的双突变体具有中等毒力表型，这与SLO引发保护性先天免疫反应的假设一致。我们得出结论，NADase和SLO共同增强了GAS在体内的毒力。
