Defining the Roles of TcdA and TcdB in Localized Gastrointestinal Disease, Systemic Organ Damage, and the Host Response during Clostridium difficile Infections
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 th...
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American Society of Microbiology
2015
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4453007/ |
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pubmed-44530072015-06-11 Defining the Roles of TcdA and TcdB in Localized Gastrointestinal Disease, Systemic Organ Damage, and the Host Response during Clostridium difficile Infections Carter, Glen P. Chakravorty, Anjana Pham Nguyen, Tu Anh Mileto, Steven Schreiber, Fernanda Li, Lucy Howarth, Pauline Clare, Simon Cunningham, Bliss Sambol, Susan P. Cheknis, Adam Figueroa, Iris Johnson, Stuart Gerding, Dale Rood, Julian I. Dougan, Gordon Lawley, Trevor D. Lyras, Dena Research Article 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. American Society of Microbiology 2015-06-02 /pmc/articles/PMC4453007/ /pubmed/26037121 http://dx.doi.org/10.1128/mBio.00551-15 Text en Copyright © 2015 Carter et al. http://creativecommons.org/licenses/by-nc-sa/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license (http://creativecommons.org/licenses/by-nc-sa/3.0/) , which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. |
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Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
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NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Carter, Glen P. Chakravorty, Anjana Pham Nguyen, Tu Anh Mileto, Steven Schreiber, Fernanda Li, Lucy Howarth, Pauline Clare, Simon Cunningham, Bliss Sambol, Susan P. Cheknis, Adam Figueroa, Iris Johnson, Stuart Gerding, Dale Rood, Julian I. Dougan, Gordon Lawley, Trevor D. Lyras, Dena |
| spellingShingle |
Carter, Glen P. Chakravorty, Anjana Pham Nguyen, Tu Anh Mileto, Steven Schreiber, Fernanda Li, Lucy Howarth, Pauline Clare, Simon Cunningham, Bliss Sambol, Susan P. Cheknis, Adam Figueroa, Iris Johnson, Stuart Gerding, Dale Rood, Julian I. Dougan, Gordon Lawley, Trevor D. Lyras, Dena Defining the Roles of TcdA and TcdB in Localized Gastrointestinal Disease, Systemic Organ Damage, and the Host Response during Clostridium difficile Infections |
| author_facet |
Carter, Glen P. Chakravorty, Anjana Pham Nguyen, Tu Anh Mileto, Steven Schreiber, Fernanda Li, Lucy Howarth, Pauline Clare, Simon Cunningham, Bliss Sambol, Susan P. Cheknis, Adam Figueroa, Iris Johnson, Stuart Gerding, Dale Rood, Julian I. Dougan, Gordon Lawley, Trevor D. Lyras, Dena |
| author_sort |
Carter, Glen P. |
| title |
Defining the Roles of TcdA and TcdB in Localized Gastrointestinal Disease, Systemic Organ Damage, and the Host Response during Clostridium difficile Infections |
| title_short |
Defining the Roles of TcdA and TcdB in Localized Gastrointestinal Disease, Systemic Organ Damage, and the Host Response during Clostridium difficile Infections |
| title_full |
Defining the Roles of TcdA and TcdB in Localized Gastrointestinal Disease, Systemic Organ Damage, and the Host Response during Clostridium difficile Infections |
| title_fullStr |
Defining the Roles of TcdA and TcdB in Localized Gastrointestinal Disease, Systemic Organ Damage, and the Host Response during Clostridium difficile Infections |
| title_full_unstemmed |
Defining the Roles of TcdA and TcdB in Localized Gastrointestinal Disease, Systemic Organ Damage, and the Host Response during Clostridium difficile Infections |
| title_sort |
defining the roles of tcda and tcdb in localized gastrointestinal disease, systemic organ damage, and the host response during clostridium difficile infections |
| description |
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. |
| publisher |
American Society of Microbiology |
| publishDate |
2015 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4453007/ |
| _version_ |
1613230959851732992 |