title: The metal homeostasis protein, Lsp, of Streptococcus pyogenes is necessary for acquisition of zinc and virulence.
abstract: "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, Zn(2+) but not Mn(2+) rescued Lsp(-) growth, implicating Zn(2+) as the physiological ligand for Lsp. Mutation of residues in the putative Zn(2+)-binding pocket generated variants both hypo- and hyper-resistant 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.
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, St Louis, Missouri 63110-1093, USA.
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Weston
authors.forename: Audrey
authors.initials: A
authors.lastname: Brenot
authors.forename: Michael G
authors.initials: MG
authors.lastname: Caparon
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001665:Binding Sites; D017353:Gene Deletion; D005816:Genetic Complementation Test; D008345:Manganese / Q000378:metabolism; D051379:Mice; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D018461:Soft Tissue Infections / Q000382:microbiology / Q000473:pathology; D013290:Streptococcal Infections / Q000382:microbiology / Q000473:pathology; D013297:Streptococcus pyogenes / Q000254:growth & development / Q000378:metabolism* / Q000472:pathogenicity*; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics / Q000502:physiology*; D015032:Zinc / Q000378:metabolism*
chemical_list: D018528:ATP-Binding Cassette Transporters; D037521:Virulence Factors; D008345:Manganese; D015032:Zinc