Cunnion Kenji M, Buescher E Stephen, Hair Pamela S
Department of Pediatrics, Eastern Virginia Medical School and Children's Hospital of The King's Daughters, Norfolk, USA.
J Lab Clin Med. 2005 Nov;146(5):279-86. doi: 10.1016/j.lab.2005.07.001.
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.
在动物模型中，补体介导的金黄色葡萄球菌调理作用是一种关键的宿主防御机制。具体而言，C3b和CD35在金黄色葡萄球菌有效的调理吞噬作用中发挥重要作用。我们已经表明，补体控制蛋白因子I介导结合在金黄色葡萄球菌表面的补体调理素C3b的裂解。在本研究中，我们通过确定因子I介导的结合于金黄色葡萄球菌的C3b裂解是否会降低中性粒细胞对金黄色葡萄球菌的吞噬作用，来检验这一观察结果的生理相关性。与对照组相比，抗因子I抗体抑制金黄色葡萄球菌表面C3b的裂解超过83%（通过iC3b生成来测定），并使金黄色葡萄球菌的吞噬作用增加超过100%。用因子I处理包被C3b的金黄色葡萄球菌会增加iC3b的生成（75%），减少结合在金黄色葡萄球菌表面的C3片段总量（58%），并减少吞噬的细菌数量（40%）。专门检测从金黄色葡萄球菌表面脱落的C3片段时，我们发现因子I增加了脱落（43%）。值得注意的是，无论是否存在已知的因子I辅因子H，这些因子I介导的效应大小相同。这些发现表明，金黄色葡萄球菌受益于，并且可能操纵因子I裂解C3b这一通常具有宿主保护作用的活性，这导致细菌逃避补体介导的调理吞噬作用。由于逃避调理吞噬作用介导的破坏是细菌导致人类疾病生存的必要机制，阻止金黄色葡萄球菌表面C3b的裂解，从而增强调理吞噬作用，是一个有前景的治疗干预潜在靶点。
