Program in Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute (HKI), 07745 Jena, Germany.
Cell Rep. 2022 Jan 4;38(1):110187. doi: 10.1016/j.celrep.2021.110187.
Candida albicans is both a commensal and an opportunistic fungal pathogen. Invading hyphae of C. albicans secrete candidalysin, a pore-forming peptide toxin. To prevent cell death, epithelial cells must protect themselves from direct damage induced by candidalysin and by the mechanical forces exerted by expanding hyphae. We identify two key Ca-dependent repair mechanisms employed by epithelial cells to withstand candidalysin-producing hyphae. Using camelid nanobodies, we demonstrate candidalysin secretion directly into the invasion pockets induced by elongating C. albicans hyphae. The toxin induces oscillatory increases in cytosolic [Ca], which cause hydrolysis of PtdIns(4,5)P and loss of cortical actin. Epithelial cells dispose of damaged membrane regions containing candidalysin by an Alg-2/Alix/ESCRT-III-dependent blebbing process. At later stages, plasmalemmal tears induced mechanically by invading hyphae are repaired by exocytic insertion of lysosomal membranes. These two repair mechanisms maintain epithelial integrity and prevent mucosal damage during both commensal growth and infection by C. albicans.
白色念珠菌既是共生菌又是机会性真菌病原体。侵袭性的白色念珠菌菌丝会分泌出一种成孔肽毒素——念珠菌溶素。为了防止细胞死亡，上皮细胞必须保护自己免受念珠菌溶素直接诱导的损伤以及由扩张菌丝产生的机械力的损伤。我们确定了上皮细胞用来抵抗产念珠菌溶素菌丝的两种关键 Ca 依赖性修复机制。使用骆驼科纳米抗体，我们证明了念珠菌溶素直接分泌到由白色念珠菌菌丝延伸形成的入侵囊中。该毒素诱导细胞质 [Ca] 呈振荡性增加，导致 PtdIns(4,5)P 水解和皮质肌动蛋白丢失。上皮细胞通过 Alg-2/Alix/ESCRT-III 依赖性起泡过程处理含有念珠菌溶素的受损膜区。在后期，由入侵菌丝机械诱导的质膜撕裂通过溶酶体膜的胞吐插入来修复。这两种修复机制在上皮细胞的共生生长和白色念珠菌感染过程中维持上皮细胞的完整性并防止黏膜损伤。
