There is growing evidence that the oral infection is associated with cardiovascular disease. Nevertheless, mechanisms involved in association are not known and bacterial role in the process is uncertain. In contrast, infective endocarditis is an extensively characterized systemic disease related to oral conditions. The role of oral streptococci in the pathogenesis of endocarditis is well established. The molecular mechanisms implicated may also occur in other forms of cardiovascular disease. Therefore infective endocarditis provides an excellent model to investigate correlations between oral infection and pathogenesis of systemic diseases. Binding of oral streptococci to human platelets has been postulated as a central mechanism in the pathogenesis of infective endocarditis. Little is known about mechanisms how bacterial adhesins interact with human platelets. We have identified a serine-rich protein SrpA from the most frequent isolates of bacterial endocarditis, Streptococcus sanguis. SrpA belongs to a growing family of serine-rich bacterial adhesins. SrpA-like proteins are found conserved across many pathogenic streptococci and staphylococci. SrpA of S. sanguis mediates bacterial adhesion to human platelets via a human platelet receptor glycoprotein Ib (GPIb). In an effort to define the role of this adhesin in the pathogenesis, we will compare the virulence of the parent strain and the mutant strain in a rabbit model of bacterial endocarditis. vWF, a multimeric glycoprotein, interacts with GPIb and collagen, play an essential role in platelet adhesion and aggregation. We posit that SrpA mimics host glycoprotein von Willebrand Factor (vWF) by interacting with GPIb and collagen, thereby plays a crucial role in bacteria induced platelet aggregation. Proposed here we will determine whether the GPIb interactive adhesin SrpA also mediates the direct binding of S. sanguis to collagen, and identify critical domains within SrpA that are responsible for GPIb and collagen binding. Identification of such functional domains will lead to a better understanding of how the streptococcal adhesin explores host receptors by molecular mimicry. This information may lead to new approaches for prevention and treatment of infective endocarditis and other cardiovascular diseases. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DE016891-02
Application #
7224858
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Lunsford, Dwayne
Project Start
2006-06-01
Project End
2009-05-31
Budget Start
2007-06-01
Budget End
2009-05-31
Support Year
2
Fiscal Year
2007
Total Cost
$176,601
Indirect Cost
Name
University of Alabama Birmingham
Department
Dentistry
Type
Schools of Dentistry
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294