Kim Hwan Keun, Falugi Fabiana, Thomer Lena, Missiakas Dominique M, Schneewind Olaf
mBio. 2015 Jan 6;6(1):e02369-14. doi: 10.1128/mBio.02369-14.
Staphylococcus aureus infection is not associated with the development of protective immunity, and disease relapses occur frequently. We hypothesize that protein A, a factor that binds immunoglobulin Fcγ and cross-links V(H)3 clan B cell receptors (IgM), is the staphylococcal determinant for host immune suppression. To test this, vertebrate IgM was examined for protein A cross-linking. High V(H)3 binding activity occurred with human and guinea immunoglobulin, whereas mouse and rabbit immunoglobulins displayed little and no binding, respectively. Establishing a guinea pig model of S. aureus bloodstream infection, we show that protein A functions as a virulence determinant and suppresses host B cell responses. Immunization with SpA(KKAA), which cannot bind immunoglobulin, elicits neutralizing antibodies that enable guinea pigs to develop protective immunity.
Staphylococcus aureus is the leading cause of soft tissue and bloodstream infections; however, a vaccine with clinical efficacy is not available. Using mice to model staphylococcal infection, earlier work identified protective antigens; however, corresponding human clinical trials did not reach their endpoints. We show that B cell receptor (IgM) cross-linking by protein A is an important immune evasion strategy of S. aureus that can be monitored in a guinea pig model of bloodstream infection. Further, immunization with nontoxigenic protein A enables infected guinea pigs to elicit antibody responses that are protective against S. aureus. Thus, the guinea pig model may support preclinical development of staphylococcal vaccines.
金黄色葡萄球菌感染与保护性免疫的发展无关，疾病复发频繁发生。我们假设蛋白A，一种结合免疫球蛋白Fcγ并交联V(H)3家族B细胞受体（IgM）的因子，是金黄色葡萄球菌导致宿主免疫抑制的决定因素。为了验证这一点，研究人员检测了脊椎动物IgM与蛋白A的交联情况。人免疫球蛋白和豚鼠免疫球蛋白表现出高V(H)3结合活性，而小鼠免疫球蛋白和兔免疫球蛋白分别表现出很少或没有结合活性。通过建立金黄色葡萄球菌血流感染的豚鼠模型，我们发现蛋白A起到毒力决定因素的作用，并抑制宿主B细胞反应。用不能结合免疫球蛋白的SpA(KKAA)进行免疫接种，可引发中和抗体，使豚鼠产生保护性免疫。
金黄色葡萄球菌是软组织和血流感染的主要原因；然而，尚无具有临床疗效的疫苗。早期利用小鼠对葡萄球菌感染进行建模的研究确定了保护性抗原；然而，相应的人体临床试验未达到终点。我们发现，蛋白A对B细胞受体（IgM）的交联是金黄色葡萄球菌的一种重要免疫逃避策略，可在血流感染的豚鼠模型中进行监测。此外，用无毒蛋白A进行免疫接种可使受感染的豚鼠产生针对金黄色葡萄球菌的保护性抗体反应。因此，豚鼠模型可能有助于金黄色葡萄球菌疫苗的临床前开发。
