gC1qR/p33 Blockade ReducesStaphylococcus aureusColonization of Target Tissues in an Animal Model of Infective Endocarditis

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Abstract
GC1qR/p33 (gC1qR) is a ubiquitously expressed cellular protein that is also found in plasma and the extracellular matrix. In addition to its role in modulating the activation of complement and kinin cascades, gC1qR has been identified as a putative host ligand for endovascular pathogens, includingStaphylococcus aureus. The present study provides evidence of the ability of soluble gC1qR to enhanceS. aureus-fibrinogen interactions via simultaneously binding fibrinogen andS. aureus. This interaction was inhibited in vitro by two monoclonal antibodies (MAbs 74.5.2 and 60.11) recognizing distinct structural and functional domains of gC1qR. To evaluate the in vivo role of gC1qR, MAbs 74.5.2 and 60.11 were used in an experimental rat model ofS. aureusendocarditis. Each MAb (100 mg/kg of body weight, given intraperitoneally) reached sustained (>60 h) and high (100 to 200 μg/ml) serum levels. Prophylaxis with MAb 60.11 or 74.5.2 caused substantial reductions inS. aureuscolonization of aortic valves, kidneys, and the spleen compared to untreated controls. However, only MAb 74.5.2 prophylaxis therapy reached statistical significance, and only sera from animals protected with MAb 74.5.2 inhibited gC1qR-mediatedS. aureusinteractions with fibrinogen. Although not statistically significant, the reductions in bacterial colonization achieved with MAb 60.11 alone and in combination with MAb 74.5.2 (versus MAb 74.5.2 alone) suggest that there are effects of gC1qR blockade onS. aureusinfective endocarditis in addition to blocking gC1qR-mediatedS. aureusbinding to fibrinogen. Such impacts may include direct modulation of complement (MAb 60.11) and kinin cascades (MAb 74.5.2) and/or activation of immune and inflammatory responses via localized immune complex formation.