DOI
https://doi.org/10.25772/P9XE-TW84
Defense Date
2013
Document Type
Thesis
Degree Name
Master of Science
Department
Microbiology & Immunology
First Advisor
Dr. Richard Marconi
Abstract
Periodontitis is a chronic inflammatory disease that affects over 116 million adults in the United States. A shift in the normal microflora occurs as periodontal disease develops resulting in a larger number of Gram-negative anaerobes and spirochetes. An increase in the oral spirochete, Treponema denticola, is highly correlated with periodontal disease progression and severity. The ability of this periopathogen to thrive in the subgingival crevice is dependent on complement evasion mechanisms. Earlier analyses demonstrated that the primary mechanism of T. denticola serum resistance is binding of the human complement regulatory protein, Factor H (FH), to the factor H-binding protein (FhbB). FH serves as cofactor in the Factor-I mediated cleavage of C3b and accelerates the decay of the C3 convertase complex, leading to downregulation of C3b production. Several pathogens bind FH, and a number of these bacterial binding proteins have been shown to bind plasminogen. Plasminogen is a plasma glycoprotein that circulates as a zymogen. Its active form, plasmin, degrades components of the extracellular matrix and cleaves complement proteins C3b and C5 inhibiting complement pathway progression. Through molecular and biochemical analyses, this study demonstrates that FhbB simultaneously binds plasminogen and FH to residues located on its positively and negatively charged surfaces, respectively, and that the two ligands do not compete for binding. This study also shows that the surface-bound plasminogen is available for proteolytic cleavage into the active serine protease plasmin. The activated plasmin could break down components of the periodontal tissue leading to increased nutrient availability and creation of a larger anaerobic environment where the bacteria can flourish, thereby promoting periodontal disease.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
December 2013