Biological function of Candida albicans Ece1 and role in host-microbe interactions

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The mucosal (oral, vaginal, gastrointestinal) epithelium is of immense importance in protecting humans against a multitude of infections as it is the initial tissue encountered by the majority of microbes. In health, this microbial-epithelial encounter results in either quiescence in the case of harmless 'commensal' microbes or activation of immunity in the case of disease-causing 'pathogenic' microbes. When these normal responses are disrupted a plethora of complications arise, which have implications beyond infection as conditions including cancer and autoimmune disease are associated with abnormal interactions between host and microbe. Given the importance of these interactions, epithelial cells possess distinct mechanisms enabling mucosal tissues to distinguish between commensal and pathogenic microbes.The fungus Candida albicans (C.alb) is an example of a microbe that can exist as a commensal in healthy people but becomes a dangerous pathogen causing severe and potentially fatal disease in unhealthy people. Indeed, Candida infections are regularly found to be the third or fourth most common hospital-acquired bloodstream infection, causing death in ~40% of individuals, and are thus a serious burden to healthcare provision. Given that the vast majority of bloodstream C.alb infections are acquired through mucosal surfaces, it is of paramount importance to understand the mechanisms by which C.alb interacts with epithelial tissues in health and to identify the fungal factors that promote infection and disease when normal responses are disrupted. Presently, we have little knowledge of the fungal factors that promote mucosal infections.Our recent work has been instrumental in understanding the mechanisms by which epithelial cells identify disease-causing C.alb and how this results in immune protection. We previously showed that C.alb infection leads to the secretion of immune activators (cytokines and chemokines) that recruit specific immune cells that protect against C.alb infection. Recently, we found that to activate this protective immune process epithelial cells recognise a specific protein (CaEce1p) on the filamentous, 'invasive' form of C.alb known as hyphae. CaEce1p is a unique hyphal protein consisting of eight repeated fragments of the same size that are individually processed by the enzyme CaKex2p. We provide strong evidence demonstrating that CaEce1p (or its individual fragments) is the critical fungal protein that informs the healthy host of the presence of a microbe that has become dangerous. This proposal aims to demonstrate the function of CaEce1p for C.alb, how CaEce1p is localised to the hyphal surface and, crucially, which fragments of CaEce1p activate epithelial cells. This will provide essential new understanding to basic fungal biology and the mechanisms that underpin C.alb-host interactions in health.This project will identify CaEce1p as a new target not only for the development of new antifungal drugs but also for the development of new vaccines, adjuvants, diagnostic tests and biomarkers for fungal infections. Of additional interest is the structural similarity between CaEce1p and the hypha-specific Rep1 protein of Ustilago maydis, which is a pathogenic plant fungus that causes smut disease in corn. Thus, the functional data obtained with CaEce1p may also provide valuable groundwork for future studies investigating plant fungal pathogenesis.