Oral Epithelial Cells Distinguish between<i>Candida</i>Species with High or Low Pathogenic Potential through MicroRNA Regulation

Abstract

Oral epithelial cells monitor microbiome composition and initiate immune response upon dysbiosis, as in the case of <i>Candida</i> imbalances. <i>Candida</i> species, such as <i>C. albicans</i> and <i>C. parapsilosis</i>, are the most prevalent yeasts in the oral cavity. Comparison of healthy oral epithelial cell responses revealed that while <i>C. albicans</i> infection robustly activated inflammation cascades, <i>C. parapsilosis</i> primarily activated various inflammation-independent pathways. In posttranscriptional regulatory processes, several miRNAs were altered by both species. For <i>C. parapsilosis</i>, the dose of yeast cells directly correlated with changes in transcriptomic responses with higher fungal burdens inducing significantly different and broader changes. MicroRNAs (miRNAs) associated with carbohydrate metabolism-, hypoxia-, and vascular development-related responses dominated with <i>C. parapsilosis</i> infection, whereas <i>C. albicans</i> altered miRNAs linked to inflammatory responses. Subsequent analyses of hypoxia-inducible factor 1α (HIF1-α) and hepatic stellate cell (HSC) activation pathways predicted target genes through which miRNA-dependent regulation of yeast-specific functions may occur, which also supported the observed species-specific responses. Our findings suggest that <i>C. parapsilosis</i> is recognized as a commensal at low doses by the oral epithelium; however, increased fungal burden activates different pathways, some of which overlap with the inflammatory processes robustly induced by <i>C. albicans</i> <b>IMPORTANCE</b> A relatively new topic within the field of immunology involves the role of miRNAs in innate as well as adaptive immune response regulation. In recent years, posttranscriptional regulation of host-pathogenic fungal interactions through miRNAs was also suggested. Our study reveals that the distinct nature of human oral epithelial cell responses toward <i>C. parapsilosis</i> and <i>C. albicans</i> is possibly due to species-specific fine-tuning of host miRNA regulatory processes. The findings of this study also shed new light on the nature of early host cell transcriptional responses to the presence of <i>C. parapsilosis</i> and highlight the species' potential inflammation-independent host activation processes. These findings contribute to our better understanding of how miRNA deregulation at the oral immunological barrier, in noncanonical immune cells, may discriminate between fungal species, particularly <i>Candida</i> species with high or low pathogenic potential.