Maslanka Jeffrey R, Londregan Jennifer A, Denny Joshua E, Hulit Ellie N, Mdluli Nontokozo V, Peritore-Galve F Christopher, Alam Md Zahidul, Alameh Mohamad-Gabriel, Lacy D Borden, Zackular Joseph P, Abt Michael C
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Immunology Graduate Group, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
bioRxiv. 2025 Aug 2:2025.07.30.667646. doi: 10.1101/2025.07.30.667646.
colonizes the gastrointestinal tract and secretes two virulence factors: toxin A (TcdA) and toxin B (TcdB). Protective immunity against 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 -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, mutant strains expressing glucosyltransferase inactive (GTX) TcdA, and/or glucosyltransferase inactive TcdB were used. Infection with TcdB or dual mutant (TcdA TcdB) restored TcdB-specific antibody responses, while infection with TcdA or TcdA TcdB 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 infection in patients.
毒素A（TcdA）和毒素B（TcdB）。由于患者易受多轮反复感染，针对感染的保护性免疫有限。决定是否产生针对TcdA和TcdB的免疫的因素仍未完全明确。我们确定，感染的小鼠会产生针对TcdA的抗体和产生IL-17A的CD4 T细胞反应，但不会产生针对TcdB的反应。为了确定抗TcdB免疫失败的机制，使用了表达葡糖基转移酶失活（GTX）的TcdA和/或葡糖基转移酶失活的TcdB的突变株。用TcdB或双突变体（TcdA TcdB）感染可恢复TcdB特异性抗体反应，而用TcdA或TcdA TcdB感染会导致TcdA特异性抗体的更早诱导。最后，用双GTX突变体感染可增强TcdA和TcdB特异性CD4 T细胞反应。这些数据表明，TcdA和TcdB的葡糖基转移酶活性阻碍了针对其自身的抗原特异性适应性免疫反应，并且可能是患者感染后高复发率的潜在机制。
