Glucosylation Drives the Innate Inflammatory Response to Clostridium difficile Toxin A.
Clostridium difficile is a major, life-threatening hospital-acquired pathogen that causes mild to severe colitis in infected individuals. The tissue destruction and inflammation which characterize C. difficile infection (CDI) are primarily due to the Rho-glucosylating toxins A and B. These toxins cause epithelial cell death and induce robust inflammatory signaling by activating the transcription factor NF-κB, leading to chemokine and cytokine secretion. The toxins also activate the inflammasome complex, which leads to secretion of the pyrogenic cytokine IL-1β. In this study, we utilized glucosylation-deficient toxin A to show that activation of the inflammasome by this toxin is dependent on Rho glucosylation, confirming similar findings reported for toxin B. We also demonstrated that tissue destruction and in vivo inflammatory cytokine production are critically dependent on the enzymatic activity of toxin A, suggesting that inhibiting toxin glucosyltransferase activity may be effective in combating this refractory disease.
Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia, USA.
Carrie A
http://orcid.org/0000-0002-8225-8261
CA
Cowardin
Department of Chemistry, Wayne State University, Detroit, Michigan, USA.
Brianna M
BM
Jackman
Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia, USA.
Zannatun
Z
Noor
Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia, USA.
Stacey L
SL
Burgess
Department of Chemistry, Wayne State University, Detroit, Michigan, USA.
Andrew L
http://orcid.org/0000-0002-5783-1097
AL
Feig
Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia, USA wap3g@virginia.edu.|Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, Virginia, USA.
William A
WA
Petri
D000818:Animals; D001427:Bacterial Toxins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D015415:Biomarkers; D016360:Clostridioides difficile / Q000276:immunology* / Q000378:metabolism*; D003015:Clostridium Infections / Q000378:metabolism* / Q000382:microbiology* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004768:Enterotoxins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D006031:Glycosylation; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism
D001427:Bacterial Toxins; D015415:Biomarkers; D016207:Cytokines; D004768:Enterotoxins; D018836:Inflammation Mediators; D016328:NF-kappa B; C041348:tcdA protein, Clostridium difficile