Functional analyses of epidemic Clostridioides difficile toxin B variants reveal their divergence in utilizing receptors and inducing pathology.
Functional analyses of epidemic Clostridioides difficile toxin B variants reveal their divergence in utilizing receptors and inducing pathology.
复制标题
对流行性艰难梭菌毒素 B 变体的功能分析揭示了它们在利用受体和诱导病理学方面的差异。
DOI：
10.1371/journal.ppat.1009197
复制
发表时间：
2021-01
期刊：
影响因子：
6.7
通讯作者：
Tao L
中科院分区：
文献类型：
--
作者：
Pan Z;Zhang Y;Luo J;Li D;Zhou Y;He L;Yang Q;Dong M;Tao L
艰难梭菌毒素B（Clostridioides difficile toxin，TcdB）是引起艰难梭菌的关键毒力因子。艰难梭菌相关疾病（CDAD），包括腹泻和伪膜性结肠炎。TcdB根据其序列变异可分为多种亚型/变体，其中四种（TcdB 1 -4）是主要流行分离株中发现的优势类型。在这里，我们发现这些变体在它们的受体偏好上高度不同：TcdB 1使用两种已知的受体CSPG 4和Frizzled（FZD）蛋白，TcdB 2选择性地使用CSPG 4，TcdB 3更喜欢使用FZD，而TcdB 4既不使用CSPG 4也不使用FZD。通过创建嵌合毒素和系统切换TcdB 1和TcdB 3之间的残基，我们确定的N-末端半胱氨酸蛋白酶结构域（CPD）的区域参与CSPG 4的识别。我们进一步评估TcdB 1 -4诱导的小鼠直肠内安装模型的病理效应。TcdB 1导致最严重的总体症状，其次是TcdB 2和TcdB 3。当比较TcdB 2和TcdB 3时，TcdB 2引起更强的水肿，而TcdB 3诱导更强的炎性细胞浸润。这些发现共同证明了受体偏好的差异，并进一步导致主要TcdB亚型的结肠病理学。艰难梭菌是医院和社区相关胃肠道感染的主要原因。该细菌产生三种外毒素，包括TcdA，TcdB和CDT，其中TcdB被认为是引起疾病的关键毒力因子。自从C.艰难梭菌在1978年首次与结核病相关感染相关联，大量临床相关菌株被表征，并且发现它们中的许多具有TcdB的一些变体形式。在这项研究中，我们检查了来自流行性C的四种主要TcdB变体。艰难菌株我们发现，这些变体是高度多样化的偏好已知的受体，CSPG 4和卷曲蛋白。通过进行系统设计的诱变研究，我们确定TcdB通过跨多个结构域的区域与CSPG 4相互作用。我们还发现，TcdB变体可以在小鼠模型中诱导可区分的病理表型，表明C。携带不同TcdB变体的艰难梭菌菌株可能表现出不同的疾病进展。我们的研究提供了新的见解，毒理学和病理学的C。艰难梭菌毒素变体。
Clostridioides difficile toxin B (TcdB) is a key virulence factor that causes C. difficile associated diseases (CDAD) including diarrhea and pseudomembranous colitis. TcdB can be divided into multiple subtypes/variants based on their sequence variations, of which four (TcdB1-4) are dominant types found in major epidemic isolates. Here, we find that these variants are highly diverse in their receptor preference: TcdB1 uses two known receptors CSPG4 and Frizzled (FZD) proteins, TcdB2 selectively uses CSPG4, TcdB3 prefers to use FZDs, whereas TcdB4 uses neither CSPG4 nor FZDs. By creating chimeric toxins and systematically switching residues between TcdB1 and TcdB3, we determine that regions in the N-terminal cysteine protease domain (CPD) are involved in CSPG4-recognition. We further evaluate the pathological effects induced by TcdB1-4 with a mouse intrarectal installation model. TcdB1 leads to the most severe overall symptoms, followed by TcdB2 and TcdB3. When comparing the TcdB2 and TcdB3, TcdB2 causes stronger oedema while TcdB3 induces severer inflammatory cell infiltration. These findings together demonstrate divergence in the receptor preference and further lead to colonic pathology for predominant TcdB subtypes. Clostridioides difficile is a major cause of nosocomial and community-associated gastrointestinal infections. The bacterium produces three exotoxins including TcdA, TcdB, and CDT, of which TcdB is known as a key virulence factor causing the diseases. Since C. difficile was first linked to antibiotic-associated infections in 1978, a large number of clinically relevant strains were characterized and many of them were found to harbor some variant forms of TcdB. In this study, we examined four predominant TcdB variants from epidemic C. difficile strains. We found that these variants are highly diverse in preference to the known receptors, CSPG4 and Frizzled proteins. By conducting a systematically designed mutagenesis study, we determined that TcdB interacts with CSPG4 via regions across multiple domains. We also found that TcdB variants could induce distinguishable pathological phenotypes in a mouse model, suggesting C. difficile strains harboring divergent TcdB variants might exhibit different disease progression. Our study provides new insights into the toxicology and pathology of C. difficile toxin variants.
登录
查看更多内容
艰难梭菌毒素B对Wnt信号传导抑制的结构洞察力B。
DOI：
10.1111/febs.14681
发表时间：
2019-03
期刊：
The FEBS journal
影响因子：
--
作者：
Chen P;Tao L;Liu Z;Dong M;Jin R
通讯作者：
Jin R
影响因子：
9.4
作者：
Kim, Heejung;Riley, Thomas V.;Park, Jong-Woo
通讯作者：
Park, Jong-Woo
影响因子：
2.3
作者：
Janoir, Claire
通讯作者：
Janoir, Claire
影响因子：
3.1
作者：
Hartley-Tassell, Lauren E.;Awad, Milena M.;Jennings, Michael P.
通讯作者：
Jennings, Michael P.
影响因子：
3.4
作者：
Genth, Harald;Pauillac, Serge;Popoff, Michel R.
通讯作者：
Popoff, Michel R.