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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL030069-11
Application #
2216570
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
1982-08-01
Project End
1996-12-31
Budget Start
1994-01-01
Budget End
1994-12-31
Support Year
11
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041418799
City
Winston-Salem
State
NC
Country
United States
Zip Code
27106
Dougherty, B A; van de Rijn, I (1994) Molecular characterization of hasA from an operon required for hyaluronic acid synthesis in group A streptococci. J Biol Chem 269:169-75
Tart, R C; van de Rijn, I (1993) Identification of the surface component of Streptococcus defectivus that mediates extracellular matrix adherence. Infect Immun 61:4994-5000
Sieling, P A; Thomas, M J; van de Rijn, I (1992) Characterization of the Streptococcus adjacens group antigen structure. J Bacteriol 174:349-54
Sieling, P A; van de Rijn, I (1991) Evaluation of the immune response in protection against experimental Streptococcus defectivus endocarditis. J Lab Clin Med 117:402-9
Tagg, J R; van de Rijn, I (1991) Inverse correlation in nutritionally variant streptococci between the production of bacteriolytic activity and sensitivity to a Streptococcus pyogenes bacteriocinlike inhibitory substance. J Clin Microbiol 29:848-9
Tart, R C; van de Rijn, I (1991) Analysis of adherence of Streptococcus defectivus and endocarditis-associated streptococci to extracellular matrix. Infect Immun 59:857-62
Sieling, P A; van de Rijn, I (1991) Purification and characterization of Streptococcus adjacens (nutritionally variant Streptococcus serotype II) group antigen. Infect Immun 59:592-9
van de Rijn, I (1988) Analysis of cross-protection between serotypes and passively transferred immune globulin in experimental nutritionally variant streptococcal endocarditis. Infect Immun 56:117-21
George, M; van de Rijn, I (1988) Purification of serotype I antigen from nutritionally variant streptococci. Infect Immun 56:1222-31
George, M; van de Rijn, I (1988) Nutritionally variant streptococcal serotype I antigen. Characterization as a lipid-substituted poly(ribitol phosphate). J Immunol 140:2008-15

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