Mouse Relapse Model of Clostridium difficile Infection
Mouse Relapse Model of Clostridium difficile Infection
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DOI：
10.1128/iai.01336-10
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发表时间：
2011-07-01
影响因子：
3.1
通讯作者：
Feng, Hanping
中科院分区：
文献类型：
--
作者：
Sun, Xingmin;Wang, Haiying;Feng, Hanping
艰难梭菌是住院患者原发性和复发性腹泻和结肠炎的病原体。该疾病主要由细菌产生的两种外毒素TcdA和TcdB引起。经常性C.艰难梭菌感染（CDI）构成了这种疾病最重要的临床问题之一，在首次发作后发生在超过20%的患者中，并且频率可能增加。然而，目前还没有成熟的CDI复发动物模型可用于研究疾病的发病机制，预防和治疗。在这里，我们报告的复发/复发CDI的常规小鼠模型的建立。我们发现，CDI的首次发作很少或没有诱导针对C的保护性抗体应答。艰难梭菌毒素和小鼠继续脱落C.艰难孢子对存活小鼠进行抗生素治疗可诱发第二次腹泻，而同时将动物再次暴露于C。艰难梭菌或孢子引起与原发感染相似的全谱CDI。此外，用免疫抑制剂治疗的小鼠容易发生更严重和暴发性复发疾病。最后，利用该模型，我们证明万古霉素仅延迟疾病复发，而针对TcdA和TcdB的中和多聚血清完全保护小鼠免于CDI复发。总之，我们已经建立了小鼠复发CDI模型，该模型允许将来研究宿主免疫应答在疾病发病机制中的作用，并允许对靶向复发疾病的新疗法进行关键测试。
Clostridium difficile is the causative agent of primary and recurrent antibiotic-associated diarrhea and colitis in hospitalized patients. The disease is caused mainly by two exotoxins, TcdA and TcdB, produced by the bacteria. Recurrent C. difficile infection (CDI) constitutes one of the most significant clinical issues of this disease, occurs in more than 20% of patients after the first episode, and may be increasing in frequency. However, there is no well-established animal model of CDI relapse currently available for studying disease pathogenesis, prevention, and therapy. Here we report the establishment of a conventional mouse model of recurrence/relapse CDI. We found that the primary episode of CDI induced little or no protective antibody response against C. difficile toxins and mice continued shedding C. difficile spores. Antibiotic treatment of surviving mice induced a second episode of diarrhea, while a simultaneous reexposure of animals to C. difficile bacteria or spores elicited a full spectrum of CDI similar to that of the primary infection. Moreover, mice treated with immunosuppressive agents were prone to more severe and fulminant recurrent disease. Finally, utilizing this model, we demonstrated that vancomycin only delayed disease recurrence, whereas neutralizing polysera against both TcdA and TcdB completely protected mice against CDI relapse. In conclusion, we have established a mouse relapse CDI model that allows for future investigations of the role of the host immune response in the disease's pathogenesis and permits critical testing of new therapeutics targeting recurrent disease.