gClqR/p33 in S. Aureus Endovascular Pathogenesis

  • Peerschke, Ellinor (PI)

Project Details

Description

In addition to their well known role in hemostasis and thrombosis, platelets and endothelial cells participate in inflammation, and react with components of the immune system. Moreover, these cells express receptors for the early complement component C1q, which may function in innate immunity by mediating the phagocytosis of invading pathogens. Preliminary data suggest that gC1qR/p33, originally described as a binding site for the globular domain of C1q, recognizes both Staphylococcus aureus protein A (SPA) and fibrinogen. Thus, we hypothesize that gC1qR/p33 participates in both direct and indirect staphylococcal interactions with platelets and endothelial cells. Since S. aureus is a major etiologic agent of endovascular infections in humans, particularly infective endocarditis, understanding the molecular mechanisms involved in infection is of considerable importance. In vitro studies are proposed using human platelets, cultured human endothelial cells, and a CHO cell line expressing cell membrane gC1qR/p33 to characterize gC1qR/p33 mediated S. aureus adhesion to cell surfaces. SPA+ and SPA- isogenic strains of S. aureus, and isogenic S. aureus strains differing in their ability to adhere to and clump fibrinogen (ClfA+, ClfA-) will be tested to elucidate the involvement of SPA and fibrinogen in this process. Purified native and recombinant gC1qR/p33 and monoclonal and polyclonal anti gC1qR antibodies are available for competing with or blocking cell surface gC1qR/p33, respectively. Specific aims are proposed 1) to characterize gC1qR/p33 -SPA binding, 2) to identify gC1qR/p33 as a platelet and endothelial cell binding site for S. aureus, 3) to examine the effect of circulating IgG and C1q on SPA-gC1qR/p33 binding, 4) to assess the role of gC1qR/p33 in S. aureus induced platelet aggregation and endothelial cell infection, and 5) to evaluate the ability of gC1qR/p33 to modulate S. aureus interactions with fibrinogen/fibrin in the extracellular matrix or on cell surfaces. Since S. aureus interactions with platelets and endothelial cells are complex and multimodal, in vivo studies are proposed using a well characterized rabbit endocarditis model to assess the role of gC1qR/p33 in S. aureus adhesion to sterile vegetations, infective lesion progression, and metastasis. Results from these studies will define a novel mechanism for S. aureus interactions at sites of endovascular damage, and may identify novel targets for therapeutic intervention.
StatusFinished
Effective start/end date1/12/0130/11/06

Funding

  • National Heart, Lung, and Blood Institute: $354,250.00
  • National Heart, Lung, and Blood Institute: $254,250.00
  • National Heart, Lung, and Blood Institute: $254,250.00
  • National Heart, Lung, and Blood Institute: $1,159,375.00

Fingerprint

Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.