The role of purified Clostridium difficile glucosylating toxins in disease pathogenesis utilizing a murine cecum injection model.
The role of purified Clostridium difficile glucosylating toxins in disease pathogenesis utilizing a murine cecum injection model.
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DOI：
10.1016/j.anaerobe.2017.10.006
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发表时间：
2017-12
期刊：
影响因子：
2.3
通讯作者：
Feng H
中科院分区：
文献类型：
--
作者：
Zhang Y;Yang Z;Gao S;Hamza T;Yfantis HG;Lipsky M;Feng H
大多数致病性艰难梭菌产生两种主要外毒素TcdA和TcdB，在不存在外毒素的情况下，细菌是非致病性的。因此，研究各毒素在致病过程中的作用具有重要意义。在使用同基因菌株的艰难梭菌感染（CDI）中，不可能精确地控制单个毒素的表达水平并排除可能在感染期间促成毒素作用的细菌因素。在这项研究中，我们利用了一个急性肠道疾病模型，通过注射纯化的毒素直接进入小鼠盲肠后，中线剖腹手术。通过临床评分和存活率评估小鼠的身体状况，通过组织学检查评估肠组织损伤和炎症。根据毒素的剂量，小鼠会出现轻度至重度结肠炎，腹泻或迅速死亡。我们发现纯化的TcdA和TcdB都能够诱导临床疾病、肠道炎症和类似于CDI的组织损伤。TcdA在诱导肠道炎症和组织损伤方面明显更快，并且在诱导小鼠严重肠道疾病和死亡结果方面比TcdB强约5倍。此外，我们发现这两种毒素对疾病的诱导有显着的协同作用。比较临床株TcdB的体内毒性，发现流行株RT 027的TcdB的毒性比其他株更强。我们的研究表明，TcdA和TcdB，独立于其他因素的C。艰难梭菌，能够引起类似于CDI的疾病，并突出了针对该疾病的疫苗和治疗剂靶向毒素的重要性。
Most pathogenic Clostridium difficile produce two major exotoxins TcdA and TcdB, in the absence of which the bacterium is non-pathogenic. While it is important to investigate the role of each toxin in the pathogenesis of C. difficile infection (CDI) using isogenic strains, it is impossible to precisely control the expression levels of individual toxins and exclude bacterial factors that may contribute to the toxins' effects during infection. In this study, we utilized an acute intestinal disease model by injecting purified toxins directly into mouse cecum after a midline laparotomy. We evaluated the physical condition of mice by clinical score and survival, and the intestinal tissue damage and inflammation by histology. Depending on the dose of the toxins, mice developed mild to severe colitis, experienced diarrhea or rapidly died. We found that both purified TcdA and TcdB were able to induce clinical disease, intestinal inflammation, and tissue damage that resembled CDI. TcdA was significantly faster in inducing intestinal inflammation and tissue damage, and was approximately five times more potent than TcdB in terms of inducing severe gut disease and death outcomes in mice. Moreover, we found that the two toxins had significant synergistic effects on disease induction. Comparison of the in vivo toxicity of TcdB from clinical strains revealed that TcdB from an epidemic RT 027 strain was more toxic than the others. Our study thus demonstrates that both TcdA and TcdB, independent of other factors from C. difficile bacterium, are able to cause disease that resembles CDI and highlights the importance of targeting both toxins for vaccines and therapeutics against the disease.
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影响因子：
3.3
作者：
Li, Shan;Shi, Lianfa;Feng, Hanping
通讯作者：
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影响因子：
64.8
作者：
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影响因子：
3.1
作者：
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Papin, Jason A.
影响因子：
29.4
作者：
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通讯作者：
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影响因子：
64.8
作者：
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通讯作者：
Rood, Julian I.