's virulence requires efficient holin-mediated toxin secretion.

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 .