Candidalysin delivery to the invasion pocket is critical for host epithelial damage induced by Candida albicans

IF 4.6 Q2 MATERIALS SCIENCE, BIOMATERIALS

ACS Applied Bio Materials Pub Date : 2021-07-10 DOI:10.1111/cmi.13378

Selene Mogavero, Frank M. Sauer, Sascha Brunke, Stefanie Allert, Daniela Schulz, Stephanie Wisgott, Nadja Jablonowski, Osama Elshafee, Thomas Krüger, Olaf Kniemeyer, Axel A. Brakhage, Julian R. Naglik, Edward Dolk, Bernhard Hube

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引用次数: 32

Abstract

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.

Take Aways

Candidalysin is a peptide toxin secreted by C. albicans causing epithelial damage.
Candidalysin delivery to host cell membranes requires specific fungal attributes.
Candidalysin accumulates in invasion pockets created by invasive hyphae.
Camelid nanobodies enabled visualisation of candidalysin in the invasion pocket.

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白色念珠菌诱导的宿主上皮损伤中，念珠菌素对侵袭袋的递送至关重要

人类致病性真菌白色念珠菌是粘膜感染的常见原因。虽然从酵母菌形态转变为菌丝形态的能力对于毒力至关重要，但菌丝形成和宿主细胞入侵本身并不足以诱导上皮损伤。相反，菌丝相关肽毒素，念珠菌素，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素足以损伤上皮细胞，但其损伤程度不及入侵的白色念珠菌菌丝。因此，我们假设需要真菌属性的组合才能将念珠菌素传递到入侵口袋，从而在感染期间充分发挥白色念珠菌的破坏潜力。利用一组已知毒力缺陷的白色念珠菌突变体，我们证明了白色念珠菌的全部损伤潜力需要将候选菌素协调地递送到入侵口袋。这一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加工和假丝酵素的分泌。为了确认念珠菌素的传递，我们产生了念珠菌素特异性的骆驼类vhs(纳米体)，并证明毒素仅在白色念珠菌诱导的入侵口袋中定位和积累。总之，一个明确的毒力属性和细胞过程的组合对于将念珠菌素运送到入侵口袋以使粘膜感染期间白色念珠菌充分发挥其损伤潜力至关重要。念珠菌素是一种由白色念珠菌分泌的肽毒素，引起上皮损伤。念珠菌素传递到宿主细胞膜需要特定的真菌属性。念珠菌素在侵入菌丝形成的侵入口袋中积累。骆驼类纳米体可以在入侵口袋中可视化候选菌素。

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来源期刊

ACS Applied Bio Materials Chemistry-Chemistry (all)

CiteScore

9.40

自引率

2.10%

发文量

464