Defining the Roles of TcdA and TcdB in Localized Gastrointestinal Disease, Systemic Organ Damage, and the Host Response during Clostridium difficile Infections.
Defining the Roles of TcdA and TcdB in Localized Gastrointestinal Disease, Systemic Organ Damage, and the Host Response during Clostridium difficile Infections.
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DOI：
10.1128/mbio.00551-15
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发表时间：
2015-06-02
期刊：
影响因子：
6.4
通讯作者：
Lyras D
中科院分区：
文献类型：
--
作者：
Carter GP;Chakravorty A;Pham Nguyen TA;Mileto S;Schreiber F;Li L;Howarth P;Clare S;Cunningham B;Sambol SP;Cheknis A;Figueroa I;Johnson S;Gerding D;Rood JI;Dougan G;Lawley TD;Lyras D
艰难梭菌是抗生素相关腹泻的主要原因，也是一种重要的动物病原体，给全球公共卫生带来负担。大多数致病菌株分泌两种外毒素，TcdA和TcdB，它们被认为是主要的毒力因子。了解这些毒素在疾病中的作用对于合理设计急需的新疗法至关重要。然而，它们对疾病的相对贡献仍然存在争议。使用三种不同的动物模型，我们发现TcdA+ TcdB−突变体的毒力与野生型（TcdA+ TcdB+）菌株相比有所减弱，而TcdA− TcdB+突变体则完全有毒力。我们还首次表明，单独的TcdB与严重的局部肠道损伤和全身器官损伤有关，这表明这种毒素可能是多器官功能障碍综合征（MODS）的发病原因，MODS是一种特征不清但往往致命的C.艰难梭菌感染（CDI）。最后，我们表明，TcdB是负责诱导体内宿主先天免疫和炎症反应的主要因素。令人惊讶的是，发现所使用的动物感染模型深刻地影响疾病结果，这一发现对新疗法的验证和未来的疾病发病机制研究具有重要的影响。总体而言，我们的结果明确表明TcdB是艰难梭菌的主要毒力因子，并为感染期间宿主对艰难梭菌的反应提供了新的见解。研究结果还强调了在研究细菌毒力机制时使用适当的，并在可能的情况下使用多种动物感染模型的重要性。艰难梭菌是腹泻相关性腹泻的主要原因，也是重要的医院病原体。TcdA和TcdB被认为是导致艰难梭菌感染（CDI）的疾病症状的主要毒力因子。然而，这些毒素对疾病的个别贡献仍然存在争议。使用三种不同的感染动物模型，我们首次表明，单独的TcdB会对肠道造成严重损伤，以及全身器官损伤，这表明这种毒素可能是导致MODS的原因，这是一种严重但知之甚少的CDI并发症。这些发现为感染期间宿主对艰难梭菌的反应提供了重要的新见解，并应指导CDI治疗急需的非抗生素疗法的合理开发。
Clostridium difficile is a leading cause of antibiotic-associated diarrhea, a significant animal pathogen, and a worldwide public health burden. Most disease-causing strains secrete two exotoxins, TcdA and TcdB, which are considered to be the primary virulence factors. Understanding the role that these toxins play in disease is essential for the rational design of urgently needed new therapeutics. However, their relative contributions to disease remain contentious. Using three different animal models, we show that TcdA+ TcdB− mutants are attenuated in virulence in comparison to the wild-type (TcdA+ TcdB+) strain, whereas TcdA− TcdB+ mutants are fully virulent. We also show for the first time that TcdB alone is associated with both severe localized intestinal damage and systemic organ damage, suggesting that this toxin might be responsible for the onset of multiple organ dysfunction syndrome (MODS), a poorly characterized but often fatal complication of C. difficile infection (CDI). Finally, we show that TcdB is the primary factor responsible for inducing the in vivo host innate immune and inflammatory responses. Surprisingly, the animal infection model used was found to profoundly influence disease outcomes, a finding which has important ramifications for the validation of new therapeutics and future disease pathogenesis studies. Overall, our results show unequivocally that TcdB is the major virulence factor of C. difficile and provide new insights into the host response to C. difficile during infection. The results also highlight the critical nature of using appropriate and, when possible, multiple animal infection models when studying bacterial virulence mechanisms. Clostridium difficile is a leading cause of antibiotic-associated diarrhea and an important hospital pathogen. TcdA and TcdB are thought to be the primary virulence factors responsible for disease symptoms of C. difficile infections (CDI). However, the individual contributions of these toxins to disease remain contentious. Using three different animal models of infection, we show for the first time that TcdB alone causes severe damage to the gut, as well as systemic organ damage, suggesting that this toxin might be responsible for MODS, a serious but poorly understood complication of CDI. These findings provide important new insights into the host response to C. difficile during infection and should guide the rational development of urgently required nonantibiotic therapeutics for the treatment of CDI.