金黄色葡萄球菌,严重且通常致命的感染的常见原因,拥有能解除宿主免疫防御的分泌因子。感染期间在体内高表达,据报道,葡萄球菌蛋白A(SpA)也有助于鼻腔定植,这可能是侵袭性感染的前奏。与宿主免疫系统的共同进化为SpA提供了Fc抗体结合位点,和Fab结合位点,其通过在许多人BCR上表达的种系编码表面负责非免疫超抗原相互作用。我们想知道成年人常见的金黄色葡萄球菌的反复暴露是否,导致记忆B细胞对SpA上其他决定因素的反应积累。因此,我们分离了SpA特定的类别转换记忆B细胞,并表征其编码VH:VL抗体基因。在SpA反应性记忆B细胞中,我们证实了VH基因的使用存在显著的偏差,保留介导SpA-超抗原相互作用的表面。我们假设这些相互作用反映了宿主免疫系统和SpA的共同进化,在感染过程中,B细胞的免疫募集非常普遍,破坏了保护性防御的增强。在这里,我们提供了第一个证据,证明人类的记忆反应是由B细胞克隆补充的,和循环抗体,独立于非免疫Fc-和Fab-结合位点与SpA决定簇结合。并行,我们证明了健康的个体,从金黄色葡萄球菌感染中恢复的患者,两者都具有具有这些常规结合特异性的循环抗体。这些发现合理化了将特殊工程改造的SpA蛋白掺入保护性疫苗的潜在效用。
Staphylococcus aureus, a common cause of serious and often fatal infections, is well-armed with secreted factors that disarm host immune defenses. Highly expressed in vivo during infection, Staphylococcal protein A (SpA) is reported to also contribute to nasal colonization that can be a prelude to invasive infection. Co-evolution with the host immune system has provided SpA with an Fc-antibody binding site, and a Fab-binding site responsible for non-immune superantigen interactions via germline-encoded surfaces expressed on many human BCRs. We wondered whether the recurrent exposures to S. aureus commonly experienced by adults, result in the accumulation of memory B-cell responses to other determinants on SpA. We therefore isolated SpA-specific class-switched memory B cells, and characterized their encoding VH : VL antibody genes. In SpA-reactive memory B cells, we confirmed a striking bias in usage for VH genes, which retain the surface that mediates the SpA-superantigen interaction. We postulate these interactions reflect co-evolution of the host immune system and SpA, which during infection results in immune recruitment of an extraordinarily high prevalence of B cells in the repertoire that subverts the augmentation of protective defenses. Herein, we provide the first evidence that human memory responses are supplemented by B-cell clones, and circulating-antibodies, that bind to SpA determinants independent of the non-immune Fc- and Fab-binding sites. In parallel, we demonstrate that healthy individuals, and patients recovering from S. aureus infection, both have circulating antibodies with these conventional binding specificities. These findings rationalize the potential utility of incorporating specially engineered SpA proteins into a protective vaccine.