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Infection and Immunity, November 2009, p. 5190-5201, Vol. 77, No. 11
0019-9567/09/$08.00+0     doi:10.1128/IAI.00420-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Streptolysin S Inhibits Neutrophil Recruitment during the Early Stages of Streptococcus pyogenes Infection ^,

Ada Lin,¹ Jennifer A. Loughman,^3, Bernd H. Zinselmeyer,² Mark J. Miller,^2* and Michael G. Caparon^3*

Department of Pediatrics,¹ Department of Pathology and Immunology,² Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, Missouri 63110-1093³

Received 15 April 2009/ Returned for modification 24 May 2009/ Accepted 10 August 2009

In contrast to infection of superficial tissues, Streptococcus pyogenes infection of deeper tissue can be associated with a significantly diminished inflammatory response, suggesting that this bacterium has the ability to both promote and suppress inflammation. To examine this, we analyzed the behavior of an S. pyogenes mutant deficient in expression of the cytolytic toxin streptolysin S (SLS^–) and evaluated events that occur during the first few hours of infection by using several models including injection of zebrafish (adults, larvae, and embryos), a transepithelial polymorphonuclear leukocyte (PMN) migration assay, and two-photon microscopy of mice in vivo. In contrast to wild-type S. pyogenes, the SLS^– mutant was associated with the robust recruitment of neutrophils and significantly reduced lethal myositis in adult zebrafish. Similarly, the mutant was attenuated in embryos in its ability to cause lethality. Infection of larva muscle allowed an analysis of inflammation in real time, which revealed that the mutant had recruited PMNs to the infection site. Analysis of transepithelial migration in vitro suggested that SLS inhibited the host cells' production of signals chemotactic for neutrophils, which contrasted with the proinflammatory effect of an unrelated cytolytic toxin, streptolysin O. Using two-photon microscopy of mice in vivo, we showed that the extravasation of neutrophils during infection with SLS^– mutant bacteria was significantly accelerated compared to infection with wild-type S. pyogenes. Taken together, these data support a role for SLS in the inhibition of neutrophil recruitment during the early stages of S. pyogenes infection.

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* Corresponding author. Mailing address for M. J. Miller: Department of Pathology and Immunology, Washington University School of Medicine, 660 S. Euclid Ave., Box 8118, Saint Louis, MO 63110-1093. Phone: (314) 362-3044. Fax: (314) 362-4096. E-mail: miller{at}pathology.wustl.edu. Mailing address for M. G. Caparon: Department of Molecular Microbiology, Washington University School of Medicine, 660 S. Euclid Ave., Box 8230, Saint Louis, MO 63110-1093. Phone: (314) 362-1485. Fax: (314) 362-3203. E-mail: caparon{at}borcim.wustl.edu

Published ahead of print on 17 August 2009.

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

Editor: A. Camilli

Present address: Department of Pediatrics, Washington University School of Medicine, 660 S. Euclid Ave., Box 8208, Saint Louis, MO 63110-1093.

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Infection and Immunity, November 2009, p. 5190-5201, Vol. 77, No. 11
0019-9567/09/$08.00+0     doi:10.1128/IAI.00420-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.