Oral Epithelial Cells Distinguish betweenCandidaSpecies 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 Candida imbalances. Candida species, such as C. albicans and C. parapsilosis, are the most prevalent yeasts in the oral cavity. Comparison of healthy oral epithelial cell responses revealed that while C. albicans infection robustly activated inflammation cascades, C. parapsilosis primarily activated various inflammation-independent pathways. In posttranscriptional regulatory processes, several miRNAs were altered by both species. For C. parapsilosis, 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 C. parapsilosis infection, whereas C. albicans 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 C. parapsilosis 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 C. albicans. IMPORTANCE 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 C. parapsilosis and C. albicans 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 C. parapsilosis 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 Candida species with high or low pathogenic potential.

Candida albicans Enhances the Progression of Oral Squamous Cell CarcinomaIn VitroandIn Vivo

“…We recently utilized OKF6/TERT2 cells to investigate non-tumor host cell responses and their microRNA (miRNA) regulatory processes (in epithelial cells) in the presence of C. albicans and C. parapsilosis . Based on these previously acquired sequencing data ( 42 ), we selected 4 oncogenes ( BCL3 , BIRC3 , ATF3 and JUN ) ( 37 , 43 , 44 ) potentially regulated by C. albicans and C. parapsilosis . The expression of these genes was analyzed in OKF6/TERT2 cells at 12 h by qPCR after C. albicans and C. parapsilosis stimulus.…”

Recent Advances in Understanding the Human Fungal Pathogen Hypoxia Response in Disease Progression

“…Recent studies have specifically linked regulation and monitoring of Candida species growth and morphology through host HIF-1α activity. In the oral cavity, epithelial cells monitor the levels of Candida species through miRNA regulation (65). Oral epithelial cells can distinguish between low and high levels of C. parapsilosis and C. albicans through miRNA regulation driven by HIF-1α (65).…”

Role of Cellular Metabolism during Candida-Host Interactions

“…Concerning ECs interactions with fungi, oral epithelial cells (OECs) have been found to upregulate metabolic reprogramming-related genes in response to fungal infections, including HIF1-α pathway during C. albicans oropharyngeal candidiasis in mice [127] or C. parapsilosis infection of human OECs [128]. Similar to what is observed in phagocytosed cells, C. albicans upregulates gluconeogenesis, the glyoxylate pathway and FAO in the late phase of interaction with OECs, which might be related to the invasion process [129].…”