Cysteine Protease-Mediated Autocleavage of Clostridium difficile Toxins Regulates Their Proinflammatory Activity.
Cysteine Protease-Mediated Autocleavage of Clostridium difficile Toxins Regulates Their Proinflammatory Activity.
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DOI：
10.1016/j.jcmgh.2018.01.022
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发表时间：
2018
影响因子：
7.2
通讯作者：
Feng H
中科院分区：
文献类型：
--
作者：
Zhang Y;Li S;Yang Z;Shi L;Yu H;Salerno-Goncalves R;Saint Fleur A;Feng H
艰难梭菌毒素A（Clostridium difficile toxin A，TcdA）和艰难梭菌毒素B（Clostridium difficile toxin B，TcdB）是艰难梭菌的主要毒力因子，可引起肠道组织损伤和炎症。虽然这两种毒素是同源的，并且共享相似的结构域结构，但TcdA通常更具炎症性，而TcdB更具细胞毒性。控制2种毒素促炎活性的毒素功能域尚不清楚。在这里，我们研究了毒素结构域的功能，调节艰难梭菌毒素的促炎活性。通过使用小鼠回肠袢模型、人体组织和免疫细胞，我们研究了对一系列嵌合毒素或缺乏特定结构域功能的毒素突变体的炎症反应。通过诱变或化学抑制阻断TcdB的自加工，同时降低毒素的细胞毒性，显著增强其在动物模型中的促炎活性。此外，一个不可切割的突变TcdB是显着更有效的比野生型毒素在人类结肠组织和免疫细胞中的促炎细胞因子的诱导。在这项研究中，我们确定了一种新的机制，调节艰难梭菌毒素的生物活性，半胱氨酸蛋白酶介导的自动加工调节毒素的促炎活性。我们的研究结果为艰难梭菌感染的发病机制和治疗方法的设计提供了新的见解。
Clostridium difficile toxin A (TcdA) and C difficile toxin toxin B (TcdB), the major virulence factors of the bacterium, cause intestinal tissue damage and inflammation. Although the 2 toxins are homologous and share a similar domain structure, TcdA is generally more inflammatory whereas TcdB is more cytotoxic. The functional domain of the toxins that govern the proinflammatory activities of the 2 toxins is unknown. Here, we investigated toxin domain functions that regulate the proinflammatory activity of C difficile toxins. By using a mouse ilea loop model, human tissues, and immune cells, we examined the inflammatory responses to a series of chimeric toxins or toxin mutants deficient in specific domain functions. Blocking autoprocessing of TcdB by mutagenesis or chemical inhibition, while reducing cytotoxicity of the toxin, significantly enhanced its proinflammatory activities in the animal model. Furthermore, a noncleavable mutant TcdB was significantly more potent than the wild-type toxin in the induction of proinflammatory cytokines in human colonic tissues and immune cells. In this study, we identified a novel mechanism of regulating the biological activities of C difficile toxins in that cysteine protease-mediated autoprocessing regulates toxins’ proinflammatory activities. Our findings provide new insight into the pathogenesis of C difficile infection and the design of therapeutics against the disease.
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影响因子：
6.7
作者：
Chumbler NM;Farrow MA;Lapierre LA;Franklin JL;Haslam DB;Goldenring JR;Lacy DB
通讯作者：
Lacy DB
影响因子：
11.8
作者：
El Feghaly, Rana E.;Stauber, Jennifer L.;Haslam, David B.
通讯作者：
Haslam, David B.
影响因子：
3.3
作者：
Li, Shan;Shi, Lianfa;Feng, Hanping
通讯作者：
Feng, Hanping
DOI：
10.1056/nejmra0707500
发表时间：
2008-10-30
期刊：
The New England journal of medicine
影响因子：
--
作者：
Kelly, Ciaran P;LaMont, J Thomas
通讯作者：
LaMont, J Thomas
影响因子：
3.1
作者：
D'Auria, Kevin M.;Kolling, Glynis L.;Papin, Jason A.
通讯作者：
Papin, Jason A.