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Infection and Immunity, October 2003, p. 5823-5830, Vol. 71, No. 10
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.10.5823-5830.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

M1 Protein Triggers a Phosphoinositide Cascade for Group A Streptococcus Invasion of Epithelial Cells

Sai Sudha Purushothaman,1 Beinan Wang,2 and P. Patrick Cleary1*

Department of Microbiology, University of Minnesota, Minneapolis, Minnesota 55455,1 Department of Biochemistry, University of Southern California, Los Angeles, California 900572

Received 6 February 2003/ Returned for modification 27 May 2003/ Accepted 4 July 2003

Invasion of nonphagocytic cells by bacteria provides a favorable niche for persistence and evasion of host defenses and antibiotics. M protein is a major virulence factor because it promotes high-frequency invasion of epithelial cells by group A Streptococcus (GAS) and also renders the bacterium resistant to phagocytosis. In this study, we investigated the role of M1 protein from serotype M1 strain 90-226 in regulating mammalian signal transduction and cytoskeletal rearrangement for bacterial entry. LY294002 and wortmannin, which are inhibitors of phosphatidylinositol 3-kinase (PI 3-K) blocked invasion of epithelial cells by GAS by 75 and 80%, respectively, but failed to inhibit invasion by Salmonella enterica serovar Typhimurium. Also, epithelial cells transiently transfected with dominant negative p85 and p110 genes, the regulatory and catalytic subunits of PI 3-K, respectively, were less able to be invaded by GAS. To separate the influence of other streptococcal virulence factors from M protein, Lactococcus lactis was engineered to express M1 protein on its surface. L. lactis(pLM1) invaded epithelial cells efficiently in vitro, and PI 3-K inhibitors blocked 90% of this invasion. Purified soluble M1 protein stimulated the formation of stress fibers and actin tuffs on epithelial cells. LY294002 and wortmannin inhibited these cellular changes. A phosphoinositide analogue also inhibited the invasion of epithelial cells by GAS. Therefore, M1 protein, either directly or via bound fibronectin, initiates signals that depend on the lipid kinase PI 3-K pathway, which paves the way for cytoskeletal rearrangement that internalize the bacterium.

* Corresponding author. Mailing address: Department of Microbiology, MMC 196, 420 Delaware Street SE, University of Minnesota, Minneapolis, MN 55455. Phone: (612) 624 3932. Fax: (612) 626-0623. E-mail: cleary{at}lenti.med.umn.edu.

Editor: J. D. Clements

Infection and Immunity, October 2003, p. 5823-5830, Vol. 71, No. 10
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.10.5823-5830.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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