Attachment of bacteria to the host tissue represents the first critical step in a process that may lead to clinically manifested infections. Extracellular pathogens attach via specific surface located MSCRAMMs (Microbial Surface Components Recognizing Adhesive Matrix Molecules) to components of the extracellular matrix. We have previously demonstrated that many Gram-positive bacteria can adhere to collagen and we identified collagen binding MSCRAMMs on S. aureus and E. faecalis called CNA and ACE, respectively. We found that these MSCRAMMs can bind to multiple sites in collagen. The structure of the collagen binding domain of CNA was determined using X-ray crystallographic methods and found to contain a collagen binding extended trench on its surface. Furthermore, we found that vaccination of mice with recombinant CNA protected the animals against S. aureus induced septic death. These results form the basis for the now proposed studies where we want to identify additional collage binding MSCRAMMs and determine the structures of CNA and ACE. We hypothesize that these MSCRAMMs and other collagen adhesion receptors such as the integrins, contain trenches on their surface that represent the collagen binding sites. This hypothesis, as well as its mechanistic implication for collagen binding, will now be examined. We will identify binding sites in collagens for different adhesion receptors and characterize the interaction of synthetic triple helix collagen peptides containing these binding sites with the receptors. Finally, we will analyze in detail the established role of CNA as a virulence factor in septic arthritis and locate the protective epitopes in this MSCRAMM.
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