Role of protein A in the evasion of host adaptive immune responses by Staphylococcus aureus.
Role of protein A in the evasion of host adaptive immune responses by Staphylococcus aureus.
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DOI：
10.1128/mbio.00575-13
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发表时间：
2013-08-27
期刊：
影响因子：
6.4
通讯作者：
Schneewind O
中科院分区：
文献类型：
--
作者：
Falugi F;Kim HK;Missiakas DM;Schneewind O
人类B细胞/抗体发育中的可遗传缺陷与金黄色葡萄球菌感染的易感性增加无关。蛋白A(SpA)是金黄色葡萄球菌的表面分子，与免疫球蛋白(Ig)的Fcγ结构域结合，并与VH3型B细胞受体(Ig)的Fab结构域交联。在这里，我们产生了金黄色葡萄球菌变异体，在SpA的五个Ig结合域中的每一个中的四个关键残基上都含有氨基酸替换。野生型金黄色葡萄球菌需要SpA与Ig结合来抵抗吞噬作用，并需要SpA介导的B细胞受体交联来阻止小鼠抗体的产生。SpaKKAA突变体不能结合Ig或IgM，被吞噬并引发B细胞对关键毒力抗原的反应，这些抗原保护动物免受金黄色葡萄球菌的致命攻击。在缺乏成熟B细胞和抗体的µMT小鼠中，金黄色葡萄球菌SpA的免疫逃避属性被取消。因此，虽然野生型金黄色葡萄球菌逃脱了宿主的免疫监视，但spaKKAA变体引起了适应性反应，以保护免受反复感染。金黄色葡萄球菌会导致反复的皮肤和血液感染，但不会引发免疫力。中性粒细胞和T细胞功能的可遗传缺陷，而不是B细胞或抗体的发育，与金黄色葡萄球菌感染的增加有关，开发基于抗体的金黄色葡萄球菌疫苗的努力到目前为止都没有成功。我们在这里表明，金黄色葡萄球菌蛋白A(SpA)的Fc、γ和VH3型Fab结合活性是金黄色葡萄球菌逃避宿主免疫监视所必需的。SPA对小鼠的毒力属性需要成熟的B细胞和免疫球蛋白。这些结果表明，抗体和B细胞在金黄色葡萄球菌感染的发病机制中起着关键作用，并为金黄色葡萄球菌疫苗的开发提供了见解。
Heritable defects in human B cell/antibody development are not associated with increased susceptibility to Staphylococcus aureus infection. Protein A (SpA), a surface molecule of S. aureus, binds the Fcγ domain of immunoglobulin (Ig) and cross-links the Fab domain of VH3-type B cell receptors (IgM). Here we generated S. aureus spa variants harboring amino acid substitutions at four key residues in each of the five Ig-binding domains of SpA. Wild-type S. aureus required SpA binding to Ig to resist phagocytosis and SpA-mediated B cell receptor cross-linking to block antibody development in mice. The spaKKAA mutant, which cannot bind Ig or IgM, was phagocytosed and elicited B cell responses to key virulence antigens that protected animals against lethal S. aureus challenge. The immune evasive attributes of S. aureus SpA were abolished in µMT mice lacking mature B cells and antibodies. Thus, while wild-type S. aureus escapes host immune surveillance, the spaKKAA variant elicits adaptive responses that protect against recurrent infection. Staphylococcus aureus causes recurrent skin and bloodstream infections without eliciting immunity. Heritable defects in neutrophil and T cell function, but not B cell or antibody development, are associated with increased incidence of S. aureus infection, and efforts to develop antibody-based S. aureus vaccines have thus far been unsuccessful. We show here that the Fcγ and VH3-type Fab binding activities of staphylococcal protein A (SpA) are essential for S. aureus escape from host immune surveillance in mice. The virulence attributes of SpA in mice required mature B cells and immunoglobulin. These results suggest that antibodies and B cells play a key role in the pathogenesis of staphylococcal infections and provide insights into the development of a vaccine against S. aureus.