title: gC1qR/p33 blockade reduces Staphylococcus aureus colonization of target tissues in an animal model of infective endocarditis.
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, including Staphylococcus aureus. The present study provides evidence of the ability of soluble gC1qR to enhance S. aureus-fibrinogen interactions via simultaneously binding fibrinogen and S. 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 of S. aureus endocarditis. Each MAb (100 mg/kg of body weight, given intraperitoneally) reached sustained (>60 h) and high (100 to 200 microg/ml) serum levels. Prophylaxis with MAb 60.11 or 74.5.2 caused substantial reductions in S. aureus colonization 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-mediated S. aureus interactions 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 on S. aureus infective endocarditis in addition to blocking gC1qR-mediated S. aureus binding 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, New York, USA. epeersch@med.cornell.edu
authors.forename: Ellinor I B
authors.initials: EI
authors.lastname: Peerschke
authors.forename: Arnold S
authors.initials: AS
authors.lastname: Bayer
authors.forename: Berhane
authors.initials: B
authors.lastname: Ghebrehiwet
authors.forename: Yan Q
authors.initials: YQ
authors.lastname: Xiong
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001021:Aortic Valve / Q000382:microbiology; D001422:Bacterial Adhesion; D015922:Complement C1q; D004195:Disease Models, Animal; D004697:Endocarditis, Bacterial / Q000382:microbiology*; D005340:Fibrinogen / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000382:microbiology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D051381:Rats; D011951:Receptors, Complement / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D013154:Spleen / Q000382:microbiology; D013203:Staphylococcal Infections / Q000382:microbiology; D013211:Staphylococcus aureus / Q000254:growth & development* / Q000378:metabolism / Q000472:pathogenicity*; D014774:Virulence
chemical_list: D000911:Antibodies, Monoclonal; D008562:Membrane Glycoproteins; D011951:Receptors, Complement; C032402:complement 1q receptor; D015922:Complement C1q; D005340:Fibrinogen