Abstract
Candida albicans is the most frequent cause of oral fungal infections. However, the exact pathogenicity mechanisms that this fungus employs are largely unknown and many of the genes expressed during oral infection are uncharacterized. In this study we sought to functionally characterize 12 previously unknown function genes associated with oral candidiasis. We generated homozygous knockout mutants for all 12 genes and analyzed their interaction with human oral epithelium in vitro. Eleven mutants caused significantly less epithelial damage and, of these, deletion of orf19.6656 (DUR31) elicited the strongest reduction in pathogenicity. Interestingly, DUR31 was not only involved in oral epithelial damage, but in multiple stages of candidiasis, including surviving attack by human neutrophils, endothelial damage and virulence in vivo. In silico analysis indicated that DUR31 encodes a sodium/substrate symporter with 13 transmembrane domains and no human homologue. We provide evidence that Dur31 transports histatin 5. This is one of the very first examples of microbial driven import of this highly cytotoxic antimicrobial peptide. Also, in contrast to wild type C. albicans, dur31Δ/Δ was unable to actively increase local environmental pH, suggesting that Dur31 lies in the extracellular alkalinization hyphal auto-induction pathway; and, indeed, DUR31 was required for morphogenesis. In agreement with this observation, dur31Δ/Δ was unable to assimilate the polyamine spermidine.
Highlights
The human oral cavity represents a discrete environmental niche, harboring a diverse and complex microbiome
We identified a novel C. albicans transporter that has no human homologue and demonstrate its role during multiple stages of candidiasis. We show that this transporter is involved in modifying environmental pH and in filamentous growth
Based on previously published transcriptional data of C. albicans during both infection of the oral cavity of HIV+ individuals and infection of reconstituted human oral epithelium [9], we identified 12 genes that were upregulated at least two-fold under one or both conditions (Table S1)
Summary
The human oral cavity represents a discrete environmental niche, harboring a diverse and complex microbiome. The initiation of oral infections is associated with the formation of elongated fungal filaments (hyphae) which can penetrate into the oral epithelium This invasion process can occur via two distinct mechanisms, induced endocytosis and active penetration [9,11,12,13]. Active penetration is dependent upon fungal viability and involves direct penetration of C. albicans hyphae into host cells or at intercellular junctions [8,11] This process is believed to be driven by mechanical pressure of the invading hyphal tip and the secretion of hydrolytic enzymes. Following these adhesion and invasion events, the fungus damages epithelial host cells, mediated by a combination of active penetration, hyphal extension and the expression of largely unknown virulence factors for deeper tissue invasion and further inter-epithelial invasion [12]. Filamentation is induced by multiple environmental cues such as temperature, pH, CO2, or contact to epithelial and endothelial
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
