NanI Sialidase Enhances the Action of Clostridium perfringens Enterotoxin in the Presence of Mucus.
NanI Sialidase Enhances the Action of Clostridium perfringens Enterotoxin in the Presence of Mucus.
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DOI：
10.1128/msphere.00848-21
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发表时间：
2021-12-22
期刊：
影响因子：
4.8
通讯作者：
Uzal FA
中科院分区：
文献类型：
--
作者：
Navarro MA;Li J;Beingesser J;McClane BA;Uzal FA
产气荚膜梭菌肠毒素（CPE）是产气荚膜梭菌F型菌株引起人类胃肠道疾病的主要毒力因子，可导致致命性肠毒血症。在 F 型疾病期间，CPE 会遇到覆盖肠道的粘附粘液层，因此当前的研究评估了 NanI 是否在存在粘附粘液的情况下增强 CPE 活性。与产生丰富粘液的衍生 HT29-MTX-E12 细胞相比，CPE 单独对产生粘液的 HT29 细胞产生更多的细胞毒性跨上皮电阻 (TEER) 和对荧光右旋糖酐 (FD) 的渗透性。然而，对于 HT29-MTX-E12 细胞，NanI 的存在显着增加了 CPE 结合和孔形成，从而增强了细胞毒性、TEER 和 FD 通透性对 CPE 影响的敏感性。当在小鼠小肠袢肠毒血症模型中测试 NanI 增强 CPE 诱导的肠毒血症的能力时，病理生理学相关的 50μg/mL 剂量的 CPE 不会杀死小鼠。然而，纯化的 NanI 的共存导致 CPE 诱导的显着致死率。当在攻击过程中同时存在 NanI 时，在用 50μg/mL CPE 攻击的小鼠血清中检测到更多的 CPE。与单独使用 CPE 攻击后相比，攻击期间 NanI 和 CPE 的共存也显着增加了肠道组织学损伤，表明 NanI 增强 CPE 诱导的肠道损伤可能会增加 CPE 吸收到血液中。总体而言，这些结果表明（i）粘液抑制 CPE 作用，（ii）NanI 可以在粘液存在的情况下增强 CPE 作用，这可能有助于解释为什么产生相对较低水平 CPE 的 F 型菌株仍然具有致病性。重要性 NanI 是由一些 F 型产气荚膜梭菌菌株产生的唾液酸酶。在这里，我们发现 NanI 可以显着增强产气荚膜梭菌肠毒素 (CPE) 的作用，CPE 是 F 型菌株引起的严重人类肠道疾病的主要毒素。这种效应可能有助于解释为什么即使某些产生少量 CPE 的 F 型菌株也具有致病性。
Clostridium perfringens enterotoxin (CPE) is the main virulence factor for C. perfringens type F strains to cause human gastrointestinal diseases, which can involve lethal enterotoxemia. During type F disease, CPE encounters an adherent mucus layer overlying the intestines, so the current study evaluated if NanI potentiates CPE activity in the presence of adherent mucus. CPE alone caused more cytotoxicity transepithelial electrical resistance (TEER) and permeability to fluorescent dextran (FD) for minimal mucus-producing HT29 cells versus that in their derivative HT29-MTX-E12 cells, which produce abundant adherent mucus. However, for HT29-MTX-E12 cells, the presence of NanI significantly increased CPE binding and pore formation, which enhanced their sensitivity to CPE effects on cytotoxicity, TEER, and FD permeability. When the ability of NanI to potentiate CPE-induced enterotoxemia was then tested in a mouse small intestinal loop enterotoxemia model, a pathophysiologically relevant 50 μg/mL dose of CPE did not kill mice. However, the copresence of purified NanI resulted in significant CPE-induced lethality. More CPE was detected in the sera of mice challenged with 50 μg/mL of CPE when NanI was copresent during challenge. The copresence of NanI and CPE during challenge also significantly increased intestinal histologic damage compared to that after challenge with CPE alone, suggesting that NanI enhancement of CPE-induced intestinal damage may increase CPE absorption into blood. Overall, these results indicate that (i) mucus inhibits CPE action and (ii) NanI can potentiate CPE action in the presence of mucus, which may help explain why type F strains that produce relatively low levels of CPE are still pathogenic. IMPORTANCE NanI is a sialidase produced by some Clostridium perfringens type F strains. Here, we found that NanI can significantly increase the action of C. perfringens enterotoxin (CPE), which is the main toxin responsible for severe human enteric disease caused by type F strains. This effect likely helps to explain why even some type F strains that produce small amounts of CPE are pathogenic.