Department of Chemical Engineering, University of Texas, Austin, Texas, USA.
Department of Molecular Biosciences, University of Texas, Austin, Texas, USA.
mBio. 2022 Aug 30;13(4):e0152722. doi: 10.1128/mbio.01527-22. Epub 2022 Aug 3.
produces an array of virulence factors, including the adenylate cyclase toxin (ACT), which is essential, immunogenic in humans, and highly conserved. Despite mediating immune-evasive functions as a leukotoxin, ACT's potential role as a protective antigen is unclear. To better understand the contributions of humoral anti-ACT immunity, we evaluated protection against Bordetella pertussis by antibodies binding structurally defined ACT epitopes in a mouse pneumonia model. An ACT-neutralizing antibody, but not a nonneutralizing antibody or an isotype control, significantly increased mouse survival after lethal challenge with B. pertussis. When modified to impair Fc effector functions, the neutralizing antibody retained protective capabilities, indicating that protection was mediated by the blockade of the interactions of ACT with its αβ integrin receptor. After infection with a lower bacterial dose, ACT neutralization synergistically reduced lung bacterial colonization levels when combined with an opsonic antibody binding the surface antigen pertactin. Notably, protection was significantly enhanced when antibodies were administered intranasally as opposed to systemically, indicating that local immune responses are key to antibody-mediated protection against ACT and pertactin. These data reconcile previous conflicting reports to indicate that neutralizing anti-ACT antibodies support the phagocytosis of opsonized B. pertussis and thereby contribute to pertussis protection . Despite high vaccine coverage in developed countries, the incidence of pertussis has increased in recent decades, often leading to severe consequences for sensitive groups, including infants. For this reason, improving the efficacy of pertussis vaccines is critical, and the addition of new antigens is a leading strategy to achieve this goal. The Bordetella pertussis adenylate cyclase toxin (ACT) acts to disarm host immunity and is considered a promising vaccine candidate since it is found in all species. In this work, we show that antibodies neutralizing ACT offer protection against pertussis. Using a murine infection model, we show that antibodies neutralizing ACT can contribute to protection against infection through synergistic interactions with antibodies recognizing current vaccine antigens. Our data can help guide the design of future vaccines, whereby the inclusion of ACT-based immunogens might increase protection against pertussis infection.
产生一系列毒力因子，包括腺苷酸环化酶毒素（ACT），它在人类中是必需的、免疫原性的，并且高度保守。尽管作为白细胞毒素介导免疫逃避功能，但 ACT 作为保护性抗原的潜在作用尚不清楚。为了更好地了解体液抗-ACT 免疫的贡献，我们在小鼠肺炎模型中评估了针对博德特氏菌百日咳的抗体结合结构定义的 ACT 表位的保护作用。一种 ACT 中和抗体，但不是非中和抗体或同种型对照，可显著增加小鼠在致命性博德特氏菌百日咳挑战后的存活率。当修饰为损害 Fc 效应功能时，该中和抗体保留了保护能力，表明保护作用是通过阻断 ACT 与其 αβ 整合素受体的相互作用来介导的。在用较低细菌剂量感染后，当与结合表面抗原 pertactin 的调理抗体联合使用时，ACT 中和协同降低肺部细菌定植水平。值得注意的是，当抗体经鼻腔给药而不是系统给药时，保护作用显著增强，表明局部免疫反应是抗体介导的针对 ACT 和 pertactin 的保护的关键。这些数据调和了以前相互矛盾的报告，表明中和抗-ACT 抗体支持调理的博德特氏菌百日咳的吞噬作用，从而有助于百日咳的保护。尽管在发达国家疫苗接种率很高，但近年来百日咳的发病率有所增加，这常常导致包括婴儿在内的敏感群体出现严重后果。因此，提高百日咳疫苗的功效至关重要，添加新抗原是实现这一目标的主要策略。博德特氏菌百日咳的腺苷酸环化酶毒素（ACT）可作用于破坏宿主免疫力，被认为是一种很有前途的疫苗候选物，因为它存在于所有物种中。在这项工作中，我们表明中和 ACT 的抗体可提供针对百日咳的保护。使用小鼠感染模型，我们表明中和 ACT 的抗体可以通过与识别当前疫苗抗原的抗体协同作用来有助于保护免受感染。我们的数据可以帮助指导未来疫苗的设计，其中包含基于 ACT 的免疫原可能会增加对百日咳感染的保护。
