Abstract
SummaryCandida 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 Ca2+-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 [Ca2+], which cause hydrolysis of PtdIns(4,5)P2 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.
Highlights
Candida albicans colonizes the mucosal surfaces of the gut, oral cavity, or vaginal tracts
Characterization of the C. albicans-containing invasion pocket When growing on epithelial monolayers, C. albicans hyphae depress the host cell surface, generating an invasion pocket reminiscent of the deformations observed in infected primary tissues (Zakikhany et al, 2007; Dalle et al, 2010)
Invasion pockets generated by extending hyphae could be identified by visualizing the entire fungus with calcofluor white (CFW), while staining exposed regions of the cell wall with Alexa Fluor-conjugated concanavalin A (ConA); the lectin is excluded from invasion pockets by the tight adherence of the fungal wall to the invaginated host membrane (Figure 1)
Summary
Candida albicans colonizes the mucosal surfaces of the gut, oral cavity, or vaginal tracts. The fungus is a commensal constituent of the microbiome of most healthy individuals. A balanced microbiome and an intact immune system are required to maintain the fungus in the commensal state, preventing invasion, epithelial damage, and mucosal infection. Superficial C. albicans mucosal infections are common. In severe cases, such as in immunocompromized patients, invasion and translocation from the gut enable the fungus to disseminate via the blood stream to internal organs, causing life-threatening infections (Perlroth et al, 2007; Pfaller and Diekema, 2007; Mayer et al, 2013). Hyphal formation per se is not sufficient to cause epithelial damage (Moyes et al, 2016)
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