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Infection and Immunity, July 2009, p. 2840-2848, Vol. 77, No. 7
0019-9567/09/$08.00+0     doi:10.1128/IAI.01299-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Metal Homeostasis Protein, Lsp, of Streptococcus pyogenes Is Necessary for Acquisition of Zinc and Virulence{triangledown} ,{dagger}

Benjamin F. Weston,1,{ddagger} Audrey Brenot,2,§ and Michael G. Caparon2*

Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110-1093,1 Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110-10932

Received 23 October 2008/ Returned for modification 4 December 2008/ Accepted 16 April 2009

"Cluster 9" family lipoproteins function as ligand-binding subunits of ABC-type transporters in maintaining transition metal homeostasis and have been implicated in the virulence of several bacteria. While these proteins share high similarity, the specific metal that they recognize and whether their role in virulence directly involves metal homeostasis cannot be reliably predicted. We examined the cluster 9 protein Lsp of Streptococcus pyogenes and found that specific deletion of lsp produced mutants highly attenuated in a murine model of soft tissue infection. Under standard in vitro conditions, growth of the Lsp– mutant was indistinguishable from that of the wild type, but growth was defective under zinc-limited conditions. The growth defect could be complemented by plasmids expressing wild-type Lsp but not Lsp engineered to lack its putative lipidation residue. Furthermore, Zn2+ but not Mn2+ rescued Lsp– growth, implicating Zn2+ as the physiological ligand for Lsp. Mutation of residues in the putative Zn2+-binding pocket generated variants both hypo- and hyperresistant to zinc starvation, and both mutant classes displayed attenuated virulence. Together, these data suggest that Lsp is a ligand-binding component of an ABC-type zinc permease and that perturbation of zinc homeostasis inhibits the ability of S. pyogenes to cause disease in a zinc-limited host milieu.

* Corresponding author. Mailing address: Department of Molecular Microbiology, Washington University School of Medicine, 660 S. Euclid Ave., Box 8230, St. Louis, MO 63110-1093. Phone: (314) 362-1485. Fax: (314) 362-3203. E-mail: caparon{at}borcim.wustl.edu

{triangledown} Published ahead of print on 27 April 2009.

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

Editor: J. N. Weiser

{ddagger} Present address: Dept. of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202-5114.

§ Present address: Dept. of Anatomy, UC San Francisco, 513 Parnassus Ave., Box 0452, San Francisco, CA 94143.

Infection and Immunity, July 2009, p. 2840-2848, Vol. 77, No. 7
0019-9567/09/$08.00+0     doi:10.1128/IAI.01299-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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