The human pathogenic fungus Candida albicans is a frequent cause of mucosal infections. Although the ability to transition from the yeast to the hypha morphology is essential for virulence, hypha formation and host cell invasion per se are not sufficient for the induction of epithelial damage. Rather, the hypha-associated peptide toxin, candidalysin, a product of the Ece1 polyprotein, is the critical damaging factor. While synthetic, exogenously added candidalysin is sufficient to damage epithelial cells, the level of damage does not reach the same level as invading C. albicans hyphae. Therefore, we hypothesized that a combination of fungal attributes is required to deliver candidalysin to the invasion pocket to enable the full damaging potential of C. albicans during infection. Utilising a panel of C. albicans mutants with known virulence defects, we demonstrate that the full damage potential of C. albicans requires the coordinated delivery of candidalysin to the invasion pocket. This process requires appropriate epithelial adhesion, hyphal extension and invasion, high levels of ECE1 transcription, proper Ece1 processing and secretion of candidalysin. To confirm candidalysin delivery, we generated camelid V_HHs (nanobodies) specific for candidalysin and demonstrate localization and accumulation of the toxin only in C. albicans-induced invasion pockets. In summary, a defined combination of virulence attributes and cellular processes is critical for delivering candidalysin to the invasion pocket to enable the full damage potential of C. albicans during mucosal infection.

中文翻译：

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念珠菌溶血素递送至侵入袋对于白色念珠菌诱导的宿主上皮损伤至关重要

人类致病性真菌白色念珠菌是黏膜感染的常见原因。尽管从酵母转变为菌丝形态的能力对于毒力是必不可少的，但菌丝形成和宿主细胞侵袭本身不足以诱导上皮损伤。相反，菌丝相关肽毒素念珠菌溶素是 Ece1 多蛋白的产物，是关键的破坏因素。虽然合成的、外源性添加的念珠菌溶血素足以损伤上皮细胞，但损伤程度并未达到与入侵白色念珠菌菌丝相同的程度。因此，我们假设需要结合真菌属性将念珠菌溶素输送到入侵袋，以充分发挥白色念珠菌的破坏潜力在感染期间。利用一组具有已知毒力缺陷的白色念珠菌突变体，我们证明白色念珠菌的全部破坏潜力需要将念珠菌溶素协调递送到入侵袋中。这个过程需要适当的上皮粘附、菌丝延伸和侵袭、高水平的ECE1转录、适当的 Ece1 加工和念珠菌溶素的分泌。为了确认念珠菌溶血素的递送，我们生成了对念珠菌溶血素特异的骆驼V _H Hs（纳米抗体），并证明了毒素仅在白色念珠菌中的定位和积累-诱导的入侵口袋。总之，毒力属性和细胞过程的明确组合对于将念珠菌溶素递送至侵入袋以使白色念珠菌在黏膜感染期间充分发挥破坏潜力至关重要。