Staphylococcus epidermidis is an emerging human pathogen that infects implanted medical devices, specially those present in immunocompromised patients. Despite its importance as a human pathogen, the virulence factors of S. epidermidis are not well characterized. Since S. epidermidis does not produce many exotoxins, we propose that its cell wall associated adhesions are essential for effective bacterial colonization and pathogenicity. Therefore, adhesins are attractive targets in the development of novel strategies to prevent and treat infections. S. epidermidis expresses two cell-wall anchored proteins, SdrG and SdrF, that are predicted to be adhesins and are similar to the S. aureus fibrinogen (Fg) binding MSCRAMMs. SdrG binds to the N-terminal residues of the Fg beta chain and is necessary for the attachment of S. epidermidis to immobilized Fg. We have solved the crystal structures of the Fg-binding region of SdrG as an apoprotein and in complex with a Fg-derived peptide. Based on these structures, we propose that SdrG changes its conformation upon ligand binding, in a series of events described in the """"""""dock, lock and latch"""""""" model. We propose that Gram-positive MSCRAMMs that have a SdrG-like predicted structure may bind to linear, peptide-like ligands with a similar mechanism. We have begun to test the """"""""dock, lock and latch"""""""" model. We propose to use several conformation-probing techniques testing SdrG as a model molecule, and subsequently apply the same principles and probe the conformational changes of other SdrG-like MSCRAMMs. In addition to the structural analysis, we will develop a murine catheter-infection model to explore the role of specific Fg-binding MSCRAMMs in S. epidermidis infections. Curiously, SdrG only binds with high affinity to human fibrinogen. Since S. epidermidis is exclusively a human pathogen, we will test if the SdrG specificity for human fibrinogen contributes to the S. epidermidis human tropism. Finally, we will examine the role of another SdrG-like protein, SdrF, as a virulence factor in S. epidermidis infections.
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| Bowden, M Gabriela; Heuck, Alejandro P; Ponnuraj, Karthe et al. (2008) Evidence for the ""dock, lock, and latch"" ligand binding mechanism of the staphylococcal microbial surface component recognizing adhesive matrix molecules (MSCRAMM) SdrG. J Biol Chem 283:638-47 |
