DiBenedetto Nicholas V, Oberkampf Marine, Crouzols Aline, Cersosimo Laura, Yeliseyev Vladimir, Bry Lynn, Peltier Johann, Dupuy Bruno
Massachusetts Host-Microbiome Center, Department Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Department of Molecular Biology and Microbiology, Tufts University Medical Center, Boston, MA, USA.
iScience. 2025 May 7;28(6):112586. doi: 10.1016/j.isci.2025.112586. eCollection 2025 Jun 20.
The human pathogen causes pseudomembranous colitis through release of the potent TcdA and TcdB toxins. These toxins lack canonical N-terminal secretion signal sequences for translocation across the bacterial membrane, suggesting alternate mechanisms of release including targeted secretion mediated by the holin-like protein TcdE and passive release from cell lysis. Here, we show how the lack of the TcdE holin profoundly reduces toxin secretion in the high toxin-producing strains UK1 and VPI10463, independently of cell lysis. Remarkably, deletion in either strain rescued highly susceptible gnotobiotic mice from lethal infection. Δ-infected mice demonstrated undetectable levels of toxin acutely and long-term survival, despite active toxin gene expression and cytoplasmic accumulation in mutant strains. These findings demonstrate the dominant role of the TcdE holin in toxin secretion and host disease and confirm the use of a conserved and non-lytic holin-mediated toxin secretion mechanism among toxigenic species of .
这种人类病原体通过释放强效毒素TcdA和TcdB引发伪膜性结肠炎。这些毒素缺乏用于跨细菌膜转运的典型N端分泌信号序列，这表明存在其他释放机制，包括由类成孔蛋白TcdE介导的靶向分泌以及细胞裂解导致的被动释放。在此，我们展示了在高毒素产生菌株UK1和VPI10463中，TcdE成孔蛋白的缺失如何显著降低毒素分泌，且与细胞裂解无关。值得注意的是，任一菌株中的缺失都使高度易感的无菌小鼠从致命感染中获救。尽管突变菌株中存在活跃的毒素基因表达和细胞质积累，但Δ感染小鼠在急性感染期毒素水平检测不到且能长期存活。这些发现证明了TcdE成孔蛋白在毒素分泌和宿主疾病中的主导作用，并证实了在产毒素的物种中使用保守的、非裂解性的成孔蛋白介导的毒素分泌机制。
