Candida albicans Pathogenicity and Epithelial Immunity

Candida species are one of the most common fungal pathogens of humans and the causative agents of superficial and invasive candidiasis. The vast majority of Candida infections are mucosal, manifesting as vaginal or oral candidiasis, which together account for an estimated 40 million infections per year. High-level Candida colonisation is also associated with several gut diseases, including Crohn's disease and ulcerative colitis, and reducing fungal burdens reduces disease severity [1]. Additionally, Candida species are an ever-increasing problem in immunocompromised patients. Furthermore , in common with the vast majority of life-threatening systemic infections, systemic Candida infections are usually acquired through mucosal surfaces. Therefore, it is of paramount importance to understand how epithelial tissues detect and restrict these pathogens to mucosal surfaces. The most common Candida species that causes human mucosal infections is Candida albicans, an endogenous commensal in approximately 50% of individuals. C. albicans is able to undergo morphological switching between a yeast and hyphal form, and the ability to switch to the hyphal form is a critical feature of pathogenicity at mucosal surfaces. Several unique hyphal proteins such as hyphal wall protein 1 (Hwp1p) and agglutinin-like sequence 3 (Als3p) have been identified as virulence attributes by promoting epithelial attachment and invasion [2]. In addition, other virulence factors that promote C. albicans pathogenicity (e. g., biofilm formation, hydrolytic enzyme production) are also linked to hypha formation. Furthermore, C. albicans strains unable to produce hyphae or maintain hypha formation are non-invasive and avirulent in vitro and in murine models of mucosal infection [3,4], indicating a key role for hypha formation in C. albicans pathogenicity. Mucosal surfaces comprise epithelial cells, which are the first line of defence against C. albicans. However, the epithelial receptors that trigger immune responses in response to this fungus are largely unknown. In oral epithelial cells, recognition of yeast and hyphal cells can occur via conventional fungal pathogen-associated molecular patterns (PAMPs) (e.g., mannans, b-glucans) and pattern recognition receptors (PRRs) (e.g., toll-like receptors, C-type lectin receptors), but activation of an immune response appears to be independent of these PAMPs and PRRs [5]. Rather, C. albicans appears to interact with epithelial-associated proteins such as E-cadherin and human epidermal growth factor receptor 2 (Her2) [6]. This recognition event triggers the induced endocytosis of C. albicans, providing a mechanism of epithelial cell entry and promoting pathogenicity. Although endocytosis is required for invasion, there is only circumstantial evidence to suggest that endocytosis directly contributes …