title: Candida albicans VPS4 contributes differentially to epithelial and mucosal pathogenesis.
abstract: We have previously demonstrated that the C. albicans pre-vacuolar protein sorting gene VPS4 is 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 VPS4 in the pathogenesis of epithelial and mucosal infection using a broad range of virulence models. The C. albicans vps4Δ mutant demonstrates reduced tolerance of cell wall stresses compared to its isogenic, complemented control strain. In an in vitro oral 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 elegans model representative of intestinal epithelial infection. In contrast, the vps4Δ mutant caused a similar degree of tissue damage in an in vitro uroepithelial model of Candida infection compared with controls. Furthermore, in an in vivo murine 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 VPS4 contributes 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 Candida vaginitis. By using a wide range of virulence models, we demonstrate that C. albicans VPS4 contributes to virulence according to the specific tissue that is infected. Thus, in order to gain a full understanding of C. albicans virulence in relation to a particular gene or pathway of interest, a selected range of infection models may need to be utilized.
authors.affiliation: a Division of Infectious Diseases ; University of New Mexico Health Science Center ; Albuquerque , NM USA.
authors.forename: Hallie S
authors.initials: HS
authors.lastname: Rane
authors.forename: Sarah
authors.initials: S
authors.lastname: Hardison
authors.forename: Claudia
authors.initials: C
authors.lastname: Botelho
authors.forename: Stella M
authors.initials: SM
authors.lastname: Bernardo
authors.forename: Floyd
authors.initials: F
authors.lastname: Wormley
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Lee
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000382:microbiology; D002176:Candida albicans / Q000235:genetics / Q000472:pathogenicity*; D002177:Candidiasis / Q000382:microbiology*; D002181:Candidiasis, Vulvovaginal / Q000382:microbiology; D002460:Cell Line; D004195:Disease Models, Animal; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics* / Q000502:physiology*; D005260:Female; D005656:Fungal Proteins / Q000235:genetics* / Q000502:physiology*; D007413:Intestinal Mucosa / Q000382:microbiology*; D008264:Macrophages / Q000382:microbiology / Q000502:physiology; D051379:Mice; D009061:Mouth Mucosa / Q000382:microbiology*; D009154:Mutation; D021381:Protein Transport; D019459:Urothelium / Q000382:microbiology*; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics* / Q000502:physiology*
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D005656:Fungal Proteins; D037521:Virulence Factors; C539750:VPS4 protein, Candida albicans
keywords: Candida albicans; LDH, lactate dehydrogenase; OEMS, oral epithelial model system; RHE, reconstituted human epithelium; SAP, secreted aspartyl protease; VPS4; protein secretion; secreted aspartyl proteases; vacuole; virulence