Abstract
Staphylococcus aureus is an important bacterial pathogen that can cause a wide spectrum of diseases in humans and other animals. S. aureus expresses a variety of virulence factors that promote infection with this pathogen. These include cell-surface proteins that mediate adherence of the bacterial cells to host extracellular matrix components, such as fibronectin and fibrinogen. Here, using immunoblotting, ELISA, and surface plasmon resonance analysis, we report that the iron-regulated surface determinant B (IsdB) protein, besides being involved in heme transport, plays a novel role as a receptor for the plasma and extracellular matrix protein vitronectin (Vn). Vn-binding activity was expressed by staphylococcal strains grown under iron starvation conditions when Isd proteins are expressed. Recombinant IsdB bound Vn dose dependently and specifically. Both near-iron transporter motifs NEAT1 and NEAT2 of IsdB individually bound Vn in a saturable manner, with KD values in the range of 16-18 nm Binding of Vn to IsdB was specifically blocked by heparin and reduced at high ionic strength. Furthermore, IsdB-expressing bacterial cells bound significantly higher amounts of Vn from human plasma than did an isdB mutant. Adherence to and invasion of epithelial and endothelial cells by IsdB-expressing S. aureus cells was promoted by Vn, and an αvβ3 integrin-blocking mAb or cilengitide inhibited adherence and invasion by staphylococci, suggesting that Vn acts as a bridge between IsdB and host αvβ3 integrin.
Highlights
Staphylococcus aureus causes a wide range of opportunistic infections that range from superficial skin infections to lifethreatening diseases, including endocarditis, pneumonia, and septicemia [1]
Bacteria grown in Roswell Park Memorial Institute 1640 (RPMI) showed a higher ability to capture Vn than those grown in iron-rich medium or in RPMI supplemented with FeCl3, suggesting that binding of strain SH1000 depends on proteins induced by iron starvation
To further analyze the interaction of Vn with S. aureus, SH1000 spa organisms grown in brain heart infusion (BHI) and RPMI medium were immobilized onto microtiter wells and allowed to interact with increasing amounts of soluble Vn (Fig. 1C)
Summary
Staphylococcus aureus causes a wide range of opportunistic infections that range from superficial skin infections to lifethreatening diseases, including endocarditis, pneumonia, and septicemia [1]. The extracellular matrix (ECM) essentially consists of macromolecules, such as collagens, proteoglycans, and glycoproteins, that serve as a substrate for the adhesion and migration of tissue cells. These processes involve integrins, a family of heterodimeric cell surface receptors that recognize specific ECM proteins [2, 3]. Vn conformational activation reveals a number of cryptic sites, including the full exposure of the heparin-binding site at the C-terminal domain of the protein [17, 18] and cell-binding motif (RGD) [19, 20]. This leads to internalization of bacteria, as exemplified by Streptococcus pneumoniae [24] or Pseudomonas aeruginosa [25], resulting in downstream signaling events [24]
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