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Journal of Bacteriology, October 2005, p. 6719-6725, Vol. 187, No. 19
0021-9193/05/$08.00+0     doi:10.1128/JB.187.19.6719-6725.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

D-Alanylation of Teichoic Acids Promotes Group A Streptococcus Antimicrobial Peptide Resistance, Neutrophil Survival, and Epithelial Cell Invasion

Sascha A. Kristian,1,2 Vivekanand Datta,1 Christopher Weidenmaier,3 Rita Kansal,4 Iris Fedtke,3 Andreas Peschel,3 Richard L. Gallo,2 and Victor Nizet1*

Department of Pediatrics, Division of Infectious Diseases, University of California, San Diego, La Jolla, California 92093,1 Division of Dermatology, University of California, San Diego, and VA San Diego Healthcare System, 3350 La Jolla Village Drive, La Jolla, California 92161,2 Cellular and Molecular Microbiology, Department of Medical Microbiology and Hygiene, University Hospitals Tübingen, 72076 Tübingen, Germany,3 Research Service, Veterans Affairs Medical Center, Memphis, Tennessee 381044

Received 24 May 2005/ Accepted 21 July 2005

Group A streptococcus (GAS) is a leading cause of severe, invasive human infections, including necrotizing fasciitis and toxic shock syndrome. An important element of the mammalian innate defense system against invasive bacterial infections such as GAS is the production of antimicrobial peptides (AMPs) such as cathelicidins. In this study, we identify a specific GAS phenotype that confers resistance to host AMPs. Allelic replacement of the dltA gene encoding D-alanine-D-alanyl carrier protein ligase in an invasive serotype M1 GAS isolate led to loss of teichoic acid D-alanylation and an increase in net negative charge on the bacterial surface. Compared to the wild-type (WT) parent strain, the GAS {Delta}dltA mutant exhibited increased susceptibility to AMP and lysozyme killing and to acidic pH. While phagocytic uptake of WT and {Delta}dltA mutants by human neutrophils was equivalent, neutrophil-mediated killing of the {Delta}dltA strain was greatly accelerated. Furthermore, we observed the {Delta}dltA mutant to be diminished in its ability to adhere to and invade cultured human pharyngeal epithelial cells, a likely proximal step in the pathogenesis of invasive infection. Thus, teichoic acid D-alanylation may contribute in multiple ways to the propensity of invasive GAS to bypass mucosal defenses and produce systemic infection.

* Corresponding author. Mailing address: Division of Pediatric Infectious Diseases, University of California, San Diego School of Medicine, Cellular & Molecular Medicine East, Room 1066, 9500 Gilman Drive, Mail Code 0687, La Jolla, CA 92093-0687. Phone: (858) 534-9760. Fax: (858) 534-5611. E-mail: vnizet{at}ucsd.edu.

Journal of Bacteriology, October 2005, p. 6719-6725, Vol. 187, No. 19
0021-9193/05/$08.00+0     doi:10.1128/JB.187.19.6719-6725.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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