Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA.
Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA
mBio. 2018 Feb 27;9(1):e00209-18. doi: 10.1128/mBio.00209-18.
Toxin neutralizing antibodies represent the major mode of protective immunity against a number of toxin-mediated bacterial diseases, including anthrax; however, the cellular mechanisms that lead to optimal neutralizing antibody responses remain ill defined. Here we show that the cellular binding pathway of anthrax protective antigen (PA), the binding component of anthrax toxin, determines the toxin neutralizing antibody response to this antigen. PA, which binds cellular receptors and efficiently enters antigen-presenting cells by receptor-mediated endocytosis, was found to elicit robust anti-PA IgG and toxin neutralizing antibody responses. In contrast, a receptor binding-deficient mutant of PA, which does not bind receptors and only inefficiently enters antigen-presenting cells by macropinocytosis, elicited very poor antibody responses. A chimeric protein consisting of the receptor binding-deficient PA mutant tethered to the binding subunit of cholera toxin, which efficiently enters cells using the cholera toxin receptor rather than the PA receptor, elicited an anti-PA IgG antibody response similar to that elicited by wild-type PA; however, the chimeric protein elicited a poor toxin neutralizing antibody response. Taken together, our results demonstrate that the antigen capture pathway can dictate the magnitudes of the total IgG and toxin neutralizing antibody responses to PA as well as the ratio of the two responses. Neutralizing antibodies provide protection against a number of toxin-mediated bacterial diseases by inhibiting toxin action. Therefore, many bacterial vaccines are designed to induce a toxin neutralizing antibody response. We have used protective antigen (PA), the binding component of anthrax toxin, as a model antigen to investigate immune mechanisms important for the induction of robust toxin neutralizing antibody responses. We found that the pathway used by antigen-presenting cells to capture PA dictates the robustness of the neutralizing antibody response to this antigen. These results provide new insights into immune mechanisms that play an important role in the induction of toxin neutralizing antibody responses and may be useful in the design of new vaccines against toxin-mediated bacterial diseases.
毒素中和抗体是许多毒素介导的细菌性疾病（包括炭疽病）的主要保护性免疫机制；然而，导致最佳中和抗体反应的细胞机制仍未得到明确界定。在这里，我们表明炭疽保护性抗原（PA）的细胞结合途径，即炭疽毒素的结合成分，决定了针对该抗原的毒素中和抗体反应。PA 结合细胞受体，并通过受体介导的内吞作用有效地进入抗原呈递细胞，结果发现它引发了强烈的抗 PA IgG 和毒素中和抗体反应。相比之下，一种受体结合缺陷的 PA 突变体，它不与受体结合，并且仅通过巨胞饮作用低效地进入抗原呈递细胞，引发了非常差的抗体反应。一种由受体结合缺陷的 PA 突变体与霍乱毒素结合亚基组成的嵌合蛋白，它通过霍乱毒素受体而不是 PA 受体有效地进入细胞，引发了类似于野生型 PA 引发的抗 PA IgG 抗体反应；然而，该嵌合蛋白引发了较差的毒素中和抗体反应。总之，我们的结果表明，抗原捕获途径可以决定针对 PA 的总 IgG 和毒素中和抗体反应的大小以及这两种反应的比例。中和抗体通过抑制毒素作用提供对许多毒素介导的细菌性疾病的保护。因此，许多细菌疫苗旨在诱导毒素中和抗体反应。我们使用保护性抗原（PA），即炭疽毒素的结合成分，作为模型抗原来研究对诱导强烈毒素中和抗体反应很重要的免疫机制。我们发现，抗原呈递细胞用来捕获 PA 的途径决定了针对该抗原的中和抗体反应的强度。这些结果为在诱导毒素中和抗体反应中发挥重要作用的免疫机制提供了新的见解，并可能有助于设计针对毒素介导的细菌性疾病的新疫苗。
