The Bartonella autotransporter CFA is a protective antigen and hypervariable target of neutralizing antibodies blocking erythrocyte infection

Antibodies are key to the clearance of Bartonella bacteremia, but the mechanisms and targets of protective antibodies are unknown and bacterial evasion strategies remain elusive. We studied experimental Bartonella taylorii infection of mice, its natural host, and investigated protective immune responses. Clearance of bacteremia depended on specific antibodies that interfere with bacterial attachment to erythrocytes. Accordingly, antibodies were effective in the absence of complement and Fc-receptors. Moreover, they formed independently of B-cell hypermutation and isotype class switch. The cloning of neutralizing monoclonal antibodies (mAbs) led to the identification of the bacterial autotransporter CFA as a protective antibody target, and vaccination against CFA protected against Bartonella bacteremia. MAb binding mapped to a region of CFA that is hypervariable in both human- and mouse-pathogenic Bartonella strains, suggesting mutational antibody evasion. These insights further our understanding of Bartonella immunity and immune evasion and elucidate mechanisms driving high Bartonella prevalence in the wild.

抗体是清除巴尔通体（Bartonella）菌血症的关键，但保护性抗体的作用机制与靶标尚不明确，细菌的逃逸策略也仍不明晰。我们以其天然宿主小鼠为模型，开展实验性泰勒巴尔通体（Bartonella taylorii）感染研究，并对保护性免疫应答进行了系统探究。研究发现，菌血症的清除依赖于能够干扰细菌黏附红细胞的特异性抗体。据此，此类抗体在缺乏补体（complement）与Fc受体（Fc-receptors）的情况下仍可发挥保护作用。此外，此类抗体的产生不依赖B细胞超突变（B-cell hypermutation）与免疫球蛋白类别转换（isotype class switch）。通过克隆中和性单克隆抗体（neutralizing monoclonal antibodies, mAbs），我们鉴定出细菌自转运蛋白CFA为保护性抗体的靶标；针对CFA的疫苗接种可有效抵御巴尔通体菌血症。单克隆抗体的结合位点定位于CFA的一个高变区域，该区域在人类致病与小鼠致病巴尔通体菌株中均存在序列变异，提示存在突变介导的抗体逃逸机制。这些研究结果加深了我们对巴尔通体免疫与免疫逃逸的认知，并阐明了驱动野生环境中巴尔通体高流行率的潜在机制。