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Infection and Immunity, March 2008, p. 978-985, Vol. 76, No. 3
0019-9567/08/$08.00+0     doi:10.1128/IAI.01354-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

A Chemokine-Degrading Extracellular Protease Made by Group A Streptococcus Alters Pathogenesis by Enhancing Evasion of the Innate Immune Response{triangledown} ,{dagger}

Paul Sumby,1 Shizhen Zhang,1 Adeline R. Whitney,2 Fabiana Falugi,3 Guido Grandi,3 Edward A. Graviss,4 Frank R. DeLeo,2 and James M. Musser1*

Center for Molecular and Translational Human Infectious Diseases Research, The Methodist Hospital Research Institute, Houston, Texas 77030,1 Laboratory of Human Bacterial Pathogenesis, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana 59840,2 Novartis Vaccines and Diagnostics, Via Fiorentina 1, 53100 Siena, Italy,3 Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 770304

Received 8 October 2007/ Returned for modification 22 November 2007/ Accepted 26 December 2007

Circumvention of the host innate immune response is critical for bacterial pathogens to infect and cause disease. Here we demonstrate that the group A Streptococcus (GAS; Streptococcus pyogenes) protease SpyCEP (S. pyogenes cell envelope protease) cleaves granulocyte chemotactic protein 2 (GCP-2) and growth-related oncogene alpha (GRO{alpha}), two potent chemokines made abundantly in human tonsils. Cleavage of GCP-2 and GRO{alpha} by SpyCEP abrogated their abilities to prime neutrophils for activation, detrimentally altering the innate immune response. SpyCEP expression is negatively regulated by the signal transduction system CovR/S. Purified recombinant CovR bound the spyCEP gene promoter region in vitro, indicating direct regulation. Immunoreactive SpyCEP protein was present in the culture supernatants of covR/S mutant GAS strains but not in supernatants from wild-type strains. However, wild-type GAS strains do express SpyCEP, where it is localized to the cell wall. Strain MGAS2221, an organism representative of the highly virulent and globally disseminated M1T1 GAS clone, differed significantly from its isogenic spyCEP mutant derivative strain in a mouse soft tissue infection model. Interestingly, and in contrast to previous studies, the isogenic mutant strain generated lesions of larger size than those formed following infection with the parent strain. The data indicate that SpyCEP contributes to GAS virulence in a strain- and disease-dependent manner.

* Corresponding author. Mailing address: Center for Molecular and Translational Human Infectious Diseases Research, The Methodist Hospital Research Institute, B490, 6565 Fannin Street, Houston, TX 77030. Phone: (713) 441-5890. Fax: (713) 441-3447. E-mail: jmmusser{at}tmhs.org

{triangledown} Published ahead of print on 3 January 2008.

{dagger} Supplemental material for this article may be found at http://iai.asm.org/.

Editor: A. Camilli

Infection and Immunity, March 2008, p. 978-985, Vol. 76, No. 3
0019-9567/08/$08.00+0     doi:10.1128/IAI.01354-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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