2. Academic Validation
  3. Clostridioides difficile toxin A and toxin B inhibit toxin-specific adaptive immune responses through glucosyltransferase-dependent activity

Clostridioides difficile toxin A and toxin B inhibit toxin-specific adaptive immune responses through glucosyltransferase-dependent activity

  • Mucosal Immunol. 2025 Aug 16:S1933-0219(25)00087-X. doi: 10.1016/j.mucimm.2025.08.004.
Jeffrey R Maslanka 1,  Jennifer A Londregan 2,  Joshua E Denny 3,  Ellie N Hulit 3,  Nontokozo V Mdluli 3,  F Christopher Peritore-Galve 4,  Md Zahidul Alam 3,  Mohamad-Gabriel Alameh 5,  D Borden Lacy 6,  Joseph P Zackular 7,  Michael C Abt 8
Affiliations

Affiliations

  • 1 Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Immunology Graduate Group, University of Pennsylvania, Philadelphia, PA, USA.
  • 2 Immunology Graduate Group, University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 3 Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 4 Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 5 Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 6 Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA.
  • 7 Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Division of Protective Immunity, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 8 Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: [email protected].
PMID: 40825509 DOI: 10.1016/j.mucimm.2025.08.004
Abstract

Clostridioides difficile colonizes the gastrointestinal tract and secretes two virulence factors: toxin A (TcdA) and toxin B (TcdB). Protective immunity against C. difficile Infection is limited as patients are susceptible to multiple rounds of recurrent infections. The factors determining whether immunity to TcdA and TcdB is generated remain incompletely defined. We determined that C. difficile-infected mice generate antibody and IL-17A-producing CD4+ T cell responses to TcdA but not TcdB. To determine the mechanism of the failed anti-TcdB immunity, C. difficile mutant strains expressing glucosyltransferase inactive (GTX) TcdA, and/or glucosyltransferase inactive TcdB were used. Infection with TcdBGTX or dual mutant (TcdAGTX TcdBGTX) restored TcdB-specific antibody responses, while Infection with TcdAGTX or TcdAGTX TcdBGTX led to an earlier induction of TcdA-specific antibodies. Finally, Infection with the dual GTX mutant enhanced TcdA and TcdB-specific CD4+ T cell responses. These data demonstrate that the glucosyltransferase activity of TcdA and TcdB hinders the antigen-specific adaptive immune response to itself and may be a mechanism that underlies high recurrence rates following C. difficile Infection in patients.

Keywords

Clostridioides difficile; IgA; Intestinal CD4 T cells; Mucosal Immunology; Toxins.

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