The role of purified Clostridium difficile glucosylating toxins in disease pathogenesis utilizing a murine cecum injection model. (December 2017)

• Record Type: Journal Article
• Authors: Zhang, Yongrong; Yang, Zhiyong; Gao, Si; Hamza, Therwa; Yfantis, Harris G.; Lipsky, Michael; Feng, Hanping
• Is Part Of: Anaerobe. Volume 48(2017)
• Page Start: 249
• Page End: 256
• Publication Date: 2017-12
• Subjects: Clostridium difficile -- Toxin A -- Toxin B -- Pathogenesis -- Cecum; Anaerobic infections -- Periodicals; Anaerobic bacteria -- Periodicals; Bacterial diseases -- Periodicals; Computer network resources; Anaerobic protozoa -- Periodicals; 579.3
• DOI: 10.1016/j.anaerobe.2017.10.006
• Languages: English
• ISSNs: 1075-9964

Abstract

Abstract: Most pathogenic Clostridium difficile produce two major exotoxins TcdA and TcdB, in the absence of which the bacterium is non-pathogenic. While it is important to investigate the role of each toxin in the pathogenesis of C. difficile infection (CDI) using isogenic strains, it is impossible to precisely control the expression levels of individual toxins and exclude bacterial factors that may contribute to the toxins' effects during infection. In this study, we utilized an acute intestinal disease model by injecting purified toxins directly into mouse cecum after a midline laparotomy. We evaluated the physical condition of mice by clinical score and survival, and the intestinal tissue damage and inflammation by histology. Depending on the dose of the toxins, mice developed mild to severe colitis, experienced diarrhea or rapidly died. We found that both purified TcdA and TcdB were able to induce clinical disease, intestinal inflammation, and tissue damage that resembled CDI. TcdA was significantly faster in inducing intestinal inflammation and tissue damage, and was approximately five times more potent than TcdB in terms of inducing severe gut disease and death outcomes in mice. Moreover, we found that the two toxins had significant synergistic effects on disease induction. Comparison of the in vivo toxicity of TcdB from clinical strains revealed that TcdB from an epidemic RT 027 strain was more toxic than the others. Our study thus demonstrates that both TcdA and TcdB, independent of other factors from C. difficile bacterium, are able to cause disease that resembles CDI and highlights the importance of targeting both toxins for vaccines and therapeutics against the disease. Highlights: TcdA and TcdB are capable of inducing diseases independently. TcdA and TcdB induce similar disease symptoms that resemble CDI. TcdA is more potent to induce severe intestinal diseases than TcdB in cecum injection model. TcdA and TcdB have synergistic effects in the disease pathogenesis. TcdB from BI/NAP1/027 strain is most virulent among the selected TcdB variants in cecum injection model.