Modelling Candida albicans infection of the human gut using human intestinal organoid cultures

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Candida albicans is recognised as the most prominent fungal commensal and pathogen of humans. C. albicans is perfectly adapted for commensalism in healthy mammalian hosts, but pathogenesis occurs when hosts develop immunodeficiency, microbial dysbiosis and epithelial damage. Susceptibility of the human intestinal epithelium to C. albicans infection is not well understood. It is likely that intestinal luminal factors, such as diet-derived and microbial metabolites released into the luminal microenvironment, act as drivers of susceptibility. At present, studies have had to rely upon mouse models or human epithelial cell lines; however, these do not completely mimic the human gut. In this project human-derived intestinal organoids will be utilised, REPLACING use of mouse models. One potential contributor to intestinal susceptibility to fungal infection is a potent intestinal toxin, the common mycotoxin food contaminant deoxynivalenol (DON). DON targets intestinal epithelial barrier integrity and pro-inflammatory signalling in human epithelial cell lines and pig intestinal explants. Furthermore, DON exposure has been shown to facilitate intestinal bacterial translocation and systemic infection by pathogenic bacteria such as Salmonella and E. coli in vitro and in vivo. This project aims to further develop our human-derived intestinal organoid model to investigate interactions of C. albicans with the human gut and to elucidate the effect of the mycotoxin DON on the susceptibility of the human intestinal epithelium to C. albicans infection. Aims:1. Develop intestinal organoids model to study the interaction of C. albicans with human gut epithelium.2. Study the effect of C. albicans on intestinal barrier function and pro-inflammatory responses.3. Investigate the effect of a diet-derived intestinal mycotoxin (deoxynivalenol, DON) on epithelial responses to C. albicans.Methodology:The project will utilise human-derived intestinal organoid cultures to assess the intestinal adhesion and infection of C. albicans and to explore the potential effects of DON. Host-fungal co-cultures will be established and intestinal function will be assessed as using trans epithelial electrical resistance, barrier protein expression and induction of cytokine release.