Toxin B is essential for virulence of Clostridium difficile.
Toxin B is essential for virulence of Clostridium difficile.
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DOI：
10.1038/nature07822
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发表时间：
2009-04-30
期刊：
影响因子：
64.8
通讯作者：
Rood, Julian I.
中科院分区：
文献类型：
--
作者：
Lyras, Dena;O'Connor, Jennifer R.;Howarth, Pauline M.;Sambol, Susan P.;Carter, Glen P.;Phumoonna, Tongted;Poon, Rachael;Adams, Vicki;Vedantam, Gayatri;Johnson, Stuart;Gerding, Dale N.;Rood, Julian I.
由于其毒力、孢子形成能力和持久性，艰难梭菌是全世界医院感染性腹泻的主要原因。艰难梭菌相关疾病（CDAD）是由抗生素治疗或正常胃肠道菌群破坏引起的。最近，由于致病菌株毒力和抗生素使用模式的变化，CDAD 导致的发病率和死亡率显着增加。自2002年以来，出现了流行性毒素III型NAP1/027菌株，其产生高水平的主要毒力因子毒素A和毒素B。这些毒素具有 63% 的氨基酸序列相似性，是梭菌糖基化毒素大家族的成员，该家族是单葡萄糖基转移酶，在人类结肠中具有促炎性、细胞毒性和肠毒性。在宿主细胞内，这两种毒素都会催化葡萄糖转移到 GTP 酶的 Rho 家族上，从而导致细胞死亡。然而，这些毒素在艰难梭菌感染中的作用尚不清楚。在这里，我们描述了艰难梭菌强毒株的同基因 tcdA 和 tcdB 突变体的构建及其在仓鼠疾病模型中的应用，以表明毒素 B 是关键的毒力决定因素。先前的研究表明，单独纯化的毒素 A 可以诱导仓鼠感染艰难梭菌后观察到的大部分病理，并且毒素 B 对动物没有毒性，除非与毒素 A 共同施用，这表明毒素具有协同作用。我们的工作提供的证据表明，毒素 B（而非毒素 A）对于毒力至关重要，这代表了重大的范式转变。此外，很明显，这些毒素在感染中的重要性不能仅通过使用纯化毒素的研究来预测，这强化了利用自然感染过程来剖析毒素在疾病中的作用的重要性。
Clostridium difficile is the leading cause of infectious diarrhea in hospitals worldwide, because of its virulence, spore-forming ability and persistence. C. difficile-associated diseases (CDAD) are induced by antibiotic treatment or disruption of the normal gastrointestinal flora. Recently, morbidity and mortality resulting from CDAD have increased significantly due to changes in the virulence of the causative strains and antibiotic usage patterns. Since 2002, epidemic toxinotype III NAP1/027 strains, which produce high levels of the major virulence factors, toxin A and toxin B, have emerged. These toxins have 63% amino acid sequence similarity and are members of the large clostridial glucosylating toxin family, which are monoglucosyltransferases that are proinflammatory, cytotoxic and enterotoxic in the human colon. Inside host cells, both toxins catalyze the transfer of glucose onto the Rho family of GTPases, leading to cell death. However, the role of these toxins in the context of a C. difficile infection is unknown. Here we describe the construction of isogenic tcdA and tcdB mutants of a virulent C. difficile strain and their use in the hamster disease model to show that toxin B is a key virulence determinant. Previous studies showed that purified toxin A alone can induce most of the pathology observed following infection of hamsters with C. difficile and that toxin B is not toxic in animals unless it is co-administered with toxin A, suggesting that the toxins act synergistically. Our work provides evidence that toxin B, not toxin A, is essential for virulence, which represents a major paradigm shift. Furthermore, it is clear that the importance of these toxins in the context of infection cannot be predicted exclusively from studies using purified toxins, reinforcing the importance of using the natural infection process to dissect the role of toxins in disease.
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影响因子：
158.5
作者：
McDonald, LC;Killgore, GE;Gerding, DN
通讯作者：
Gerding, DN
影响因子：
64.8
作者：
JUST, I;SELZER, J;AKTORIES, K
通讯作者：
AKTORIES, K
影响因子：
3.6
作者：
Matamouros, Susana;England, Patrick;Dupuy, Bruno
通讯作者：
Dupuy, Bruno
影响因子：
3.5
作者：
INOUE, H;NOJIMA, H;OKAYAMA, H
通讯作者：
OKAYAMA, H
影响因子：
3.6
作者：
O'Connor, Jennifer R.;Lyras, Dena;Rood, Julian I.
通讯作者：
Rood, Julian I.