DiBenedetto N V, Oberkampf M, Cersosimo L, Yeliseyev V, Bry L, Peltier J, Dupuy B
Massachusetts Host-Microbiome Center, Dept. Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Institut Pasteur, Université Paris-Cité, UMR-CNRS 6047, Laboratoire Pathogenèse des Bactéries Anaérobies, F-75015 Paris, France.
bioRxiv. 2023 Sep 16:2023.09.16.558055. doi: 10.1101/2023.09.16.558055.
is the leading cause of healthcare associated infections. The Pathogenicity Locus (PaLoc) toxins TcdA and TcdB promote host disease. These toxins lack canonical N-terminal signal sequences for translocation across the bacterial membrane, suggesting alternate mechanisms of release, which have included targeted secretion and passive release from cell lysis. While the holin TcdE has been implicated in TcdA and TcdB release, its role remains unknown. Here, we show profound reductions in toxin secretion in mutants in the highly virulent strains UK1 (epidemic ribotype 027, Clade 3) and VPI10463 (ribotype 087, Clade 1). Notably, deletion in either strain rescued highly susceptible gnotobiotic mice from lethal infection by reducing acute extracellular toxin to undetectable levels, limiting mucosal damage, and enabling long-term survival, in spite of continued toxin gene expression in mutants. Our findings confirm TcdE's critical functions for toxin secretion and virulence.
是医疗保健相关感染的主要原因。致病位点（PaLoc）毒素TcdA和TcdB会引发宿主疾病。这些毒素缺乏用于跨细菌膜转运的典型N端信号序列，这表明存在其他释放机制，包括靶向分泌和细胞裂解后的被动释放。虽然溶血素TcdE与TcdA和TcdB的释放有关，但其作用仍不清楚。在这里，我们发现高毒力菌株UK1（流行核糖型027，进化枝3）和VPI10463（核糖型087，进化枝1）的突变体中毒素分泌大幅减少。值得注意的是，任一菌株中的缺失通过将急性细胞外毒素降低到无法检测的水平，挽救了高度易感的无菌小鼠免于致命感染，限制了粘膜损伤，并使小鼠能够长期存活，尽管突变体中毒素基因持续表达。我们的研究结果证实了TcdE在毒素分泌和毒力方面的关键功能。
