부산대학교 도서관

We have previously demonstrated that the C. albicanspre-vacuolar protein sorting gene VPS4is required for extracellular secretion of the secreted aspartyl proteases Sap2p and Saps4–6p. Furthermore, the vps4Δ null mutant has been shown to be markedly hypovirulent in a murine tail vein model of disseminated candidiasis. In these experiments, we sought to further define the role of the pre-vacuolar secretion pathway mediated by the pre-vacuolar sorting gene VPS4in the pathogenesis of epithelial and mucosal infection using a broad range of virulence models. The C. albicansvps4Δ mutant demonstrates reduced tolerance of cell wall stresses compared to its isogenic, complemented control strain. In an in vitrooral epithelial model (OEM) of tissue invasion, the vps4Δ mutant caused reduced tissue damage compared to controls. Further, the vps4Δ mutant was defective in macrophage killing in vitro, and was attenuated in virulence in an in vivo Caenorhabditis elegansmodel representative of intestinal epithelial infection. In contrast, the vps4Δ mutant caused a similar degree of tissue damage in an in vitrouroepithelial model of Candidainfection compared with controls. Furthermore, in an in vivomurine model of vaginal candidiasis there was no reduction in fungal colony burden and no differences in vaginal histopathology compared to wild-type and complemented controls. These results suggest that VPS4contributes to several key aspects of oral epithelial but not uroepithelial infection, and in contrast to systemic infection, plays no major role in the pathogenesis of Candidavaginitis. By using a wide range of virulence models, we demonstrate that C. albicansVPS4contributes to virulence according to the specific tissue that is infected. Thus, in order to gain a full understanding of C. albicansvirulence in relation to a particular gene or pathway of interest, a selected range of infection models may need to be utilized.