Serum complement factor I decreases Staphylococcus aureus phagocytosis.
Complement-mediated opsonization of Staphylococcus aureus is a critical host defense in animal models. Specifically, C3b and CD35 play important roles in effective opsonophagocytosis of S. aureus. We have shown that complement control protein factor I mediates cleavage of the complement opsonin C3b bound to the S. aureus surface. In this study, we examined the physiologic relevance of this observation by determining whether factor I-mediated cleavage of S. aureus-bound C3b decreased phagocytosis of S. aureus by neutrophils. Compared with controls, anti-factor I antibody inhibited C3b-cleavage on the S. aureus surface by >83% (as measured by iC3b generation) and increased phagocytosis of S. aureus by >100%. Treatment of C3b-coated S. aureus with factor I increased generation of iC3b (75%), decreased the total amount of C3-fragments bound to the S. aureus surface (58%), and decreased the number of bacteria phagocytosed (40%). Testing specifically for C3-fragments shed from the S. aureus surface, we found that factor I increased shedding (43%). Notably, these factor I-mediated effects were of the same magnitude regardless of whether factor H, a known cofactor for factor I, was present. These findings indicate that S. aureus benefits from, and possibly manipulates, the normally host-protective activity of factor I cleavage of C3b, which results in bacterial escape from complement-mediated opsonophagocytosis. Because escaping opsonophagocytosis-mediated destruction is a necessary mechanism for bacterial survival resulting in human disease, preventing cleavage of C3b on the S. aureus surface, and thereby enhancing opsonophagocytosis, is a promising potential target for therapeutic intervention.
Cunnion
Kenji M
KM
Department of Pediatrics, Eastern Virginia Medical School and Children's Hospital of The King's Daughters, Norfolk, USA. cunniok@chkd.org
Buescher
E Stephen
ES
Hair
Pamela S
PS
D019138:Antibodies, Blocking / Q000494:pharmacology; D003179:Complement C3b / Q000276:immunology*; D017244:Complement Factor I / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology*; D009895:Opsonin Proteins; D010587:Phagocytosis; D013211:Staphylococcus aureus / Q000187:drug effects / Q000276:immunology*
D019138:Antibodies, Blocking; D009895:Opsonin Proteins; D003179:Complement C3b; D017244:Complement Factor I