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首页> 外文期刊>Infection and immunity >Immunization with Bacillus Spores Expressing Toxin A Peptide Repeats Protects against Infection with Clostridium difficile Strains Producing Toxins A and B
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Immunization with Bacillus Spores Expressing Toxin A Peptide Repeats Protects against Infection with Clostridium difficile Strains Producing Toxins A and B

机译：表达毒素A肽的芽孢杆菌孢子的重复免疫可防止艰难梭菌菌株产生毒素A和B的感染。

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Clostridium difficile is a leading cause of nosocomial infection in the developed world. Two toxins, A and B, produced by most strains of C. difficile are implicated as virulence factors, yet only recently has the requirement of these for infection been investigated by genetic manipulation. Current vaccine strategies are focused mostly on parenteral delivery of toxoids. In this work, we have used bacterial spores (Bacillus subtilis) as a delivery vehicle to evaluate the carboxy-terminal repeat domains of toxins A and B as protective antigens. Our findings are important and show that oral immunization of the repeat domain of toxin A is sufficient to confer protection in a hamster model of infection designed to closely mimic the human course of infection. Importantly, neutralizing antibodies to the toxin A repeat domain were shown to be cross-reactive with the analogous domain of toxin B and, being of high avidity, provided protection against challenge with a C. difficile strain producing toxins A and B (A+B+). Thus, although many strains produce both toxins, antibodies to only toxin A can mediate protection. Animals vaccinated with recombinant spores were fully able to survive reinfection, a property that is particularly important for a disease with which patients are prone to relapse. We show that mucosal immunization, not parenteral delivery, is required to generate secretory IgA and that production of these neutralizing polymeric antibodies correlates with protection. This work demonstrates that an effective vaccine against C. difficile can be designed around two attributes, mucosal delivery and the repeat domain of toxin A.
机译：艰难梭菌是发达国家中医院感染的主要原因。大多数艰难梭菌菌株产生的两种毒素A和B被认为是毒力因子，但直到最近才通过基因操作研究了它们对感染的需求。当前的疫苗策略主要集中在肠胃外递送类毒素。在这项工作中，我们已经使用细菌芽孢（枯草芽孢杆菌）作为传递载体来评估毒素A和B的羧基末端重复域作为保护性抗原。我们的发现很重要，并且表明毒素A重复结构域的口服免疫足以在仓鼠感染模型中提供保护，该模型被设计为模仿人类的感染过程。重要的是，针对毒素A重复域的中和抗体显示与毒素B的类似域具有交叉反应性，并且具有高亲和力，可抵抗产生艰难梭菌菌株的毒素A和B（A + B + ）。因此，尽管许多菌株产生两种毒素，但是仅针对毒素A的抗体可以介导保护作用。接种重组孢子的动物完全能够幸免于再次感染，这一特性对于患者容易复发的疾病特别重要。我们表明粘膜免疫，而不是非肠道递送，是产生分泌型IgA所必需的，这些中和的聚合抗体的产生与保护相关。这项工作表明，可以针对粘膜递送和毒素A的重复域这两个属性设计有效的抗艰难梭菌疫苗。

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