Subacute bacterial endocarditis is a serious disease which accounts for 0.3-3.0/1000 of all hospital admissions and the viridans streptococci remain the most frequent cause of bacterial endocarditis. Since 1961 a new group of organisms were recognized, the nutritionally variant streptococci, which cause approximately 5-10% of all cases of streptococcal endocarditis. The NVS are important pathogens of bacterial endocarditis since patients present with a higher degree of antimicrobial failure, relapse and fatality than other forms of viridans endocarditis. The overall objective of the research program is to continue a systematic study of the surface components of nutritionally variant streptococci (NVS) in order to better understand the interaction of these bacteria with the heart valves in infective subacute bacterial endocarditis. Toward this objective we plan to: 1. Complete the structural analysis of the Streptococcus defectivus and Streptococcus adjacent group antigens. 2. Determine the identity of the S. defectivus adhesion(s) responsible far the adherence of the organisms to extracellular matrix. Isolate and purify the adhesion by standard purification protocols (monoclonal antibody and affinity chromatography, hydrophobic, ion exchange, gel permeation chromatography) and/or molecular cloning (lambda gtll or cosmid libraries). 3. Identify the binding domain on the adhesion (peptide inhibition studies and specific removal of anti-adhesion antibody) and the corresponding extracellular matrix receptor(s) responsible for adherence of S. defectivus strains (photoreactive cross- linking studies, monoclonal antibodies, immunoblots). 4. Determine the role of the adhesion(s) in protection against S. defectivus endocarditis. The rat endocarditis model will be used to analyze the role of the adhesion in initiation of endocarditis. Transposon-inactivation and or nitrous acid deletion mutants also will be compared to parent strains in the model. Finally the role of anti-adhesion antibody will be determined in protection against NVS endocarditis.
The specific aims commence with a structural and immunochemical analysis of the surface components of these strains and end with the study of their structure-function relationship in the attachment to and colonization of the heart valve, a primary step in the pathogenesis of microbial endocarditis. Completion of these specific aims will permit investigators to better understand the interaction between the surface of NVS and cardiac valves. Finally, knowledge gained through these studies could lay the groundwork for a vaccine which would be beneficial to the population at high risk for this disease.
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