title: Staphylococcus aureus IsdB is a hemoglobin receptor required for heme iron utilization.
abstract: The pathogenesis of human infections caused by the gram-positive microbe Staphylococcus aureus has been previously shown to be reliant on the acquisition of iron from host hemoproteins. The iron-regulated surface determinant system (Isd) encodes a heme transport apparatus containing three cell wall-anchored proteins (IsdA, IsdB, and IsdH) that are exposed on the staphylococcal surface and hence have the potential to interact with human hemoproteins. Here we report that S. aureus can utilize the host hemoproteins hemoglobin and myoglobin, but not hemopexin, as iron sources for bacterial growth. We demonstrate that staphylococci capture hemoglobin on the bacterial surface via IsdB and that inactivation of isdB, but not isdA or isdH, significantly decreases hemoglobin binding to the staphylococcal cell wall and impairs the ability of S. aureus to utilize hemoglobin as an iron source. Stable-isotope-tracking experiments revealed removal of heme iron from hemoglobin and transport of this compound into staphylococci. Importantly, mutants lacking isdB, but not isdH, display a reduction in virulence in a murine model of abscess formation. Thus, IsdB-mediated scavenging of iron from hemoglobin represents an important virulence strategy for S. aureus replication in host tissues and for the establishment of persistent staphylococcal infections.
authors.affiliation: Department of Microbiology and Immunology, Vanderbilt University Medical School, 21st Avenue South, Medical Center North, Room A-5211, Nashville, TN 37232, USA.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Torres
authors.forename: Gleb
authors.initials: G
authors.lastname: Pishchany
authors.forename: Munir
authors.initials: M
authors.lastname: Humayun
authors.forename: Olaf
authors.initials: O
authors.lastname: Schneewind
authors.forename: Eric P
authors.initials: EP
authors.lastname: Skaar
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial; D006418:Heme / Q000737:chemistry / Q000378:metabolism*; D006454:Hemoglobins / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D009211:Myoglobin / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D013203:Staphylococcal Infections / Q000382:microbiology; D013211:Staphylococcus aureus / Q000235:genetics / Q000254:growth & development / Q000378:metabolism / Q000472:pathogenicity*; D014774:Virulence
chemical_list: D027682:Cation Transport Proteins; D006454:Hemoglobins; C510010:IsdB protein, Staphylococcus aureus; D009211:Myoglobin; D011956:Receptors, Cell Surface; D006418:Heme; D007501:Iron