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Infection and Immunity, October 2005, p. 6562-6566, Vol. 73, No. 10
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.10.6562-6566.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Role of NADase in Virulence in Experimental Invasive Group A Streptococcal Infection

Angela L. Bricker,1* Vincent J. Carey,1 and Michael R. Wessels1,2

Channing Laboratory, Brigham and Women's Hospital,1 Division of Infectious Diseases, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts2

Received 10 January 2005/ Returned for modification 17 May 2005/ Accepted 5 July 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.

* Corresponding author. Present address: U. S. Department of Agriculture, Agricultural Research Service, Eastern Regional Research Center, 600 East Mermaid Lane, Wyndmoor, PA 19038. Phone: (215) 233-6641. Fax: (215) 233-6795. E-mail: abricker{at}arserrc.gov.

Editor: V. J. DiRita

Infection and Immunity, October 2005, p. 6562-6566, Vol. 73, No. 10
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.10.6562-6566.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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