Fungi such as Candida albicans are ubiquitous colonizers of human skin and mucosa. Fungal pathogens invade the host when host defence is diminished, and the combination of fungal and bacterial colonization modulates mucosal and systemic immune responses. Little is known of the complex interaction between fungal and bacterial colonization, as well as between these two and the host genome and immunity. The Hypothesis of this proposal is that immunity to C. albicans is determined by the interaction between fungal colonization (mycobiome), bacterial flora (bacteriome), and the genetic background of the host (genome). This interaction is distorted in patients with fungal infections, and the identification of these imbalances will lead to novel therapeutic targets.The Key Objectives are:1) To map the landscape of interaction between the fungal colonization (mycobiome), bacterial flora (bacteriome) and the genetic and immunological make-up of the host (functional genome).2) To assess the dysregulation of these interactions in patients with the two most important Candida infections: recurrent vulvovaginal candidiasis (RVVC) and disseminated candidiasis.Methodological approach:- the mycobiome and bacteriome will be determined on the skin and mucosal surfaces of healthy volunteers, RVVC and disseminated candidiasis patients.- functional assessment of antifungal immune mechanisms will be correlated with the mycobiome/bacteriome, and with the host genetic variation (genome).- validation of the functional interactions of microbial communities with host immunity using focused genotyping and follow-up pathway activity screening in human cell cultures and experimental models.- microbiome/functional genome dysregulation between healthy individuals and patients with muocosla and systemic candidiasis will be identified.Expected results: Proof-of-concept in-vitro and experimental studies will validate these interactions as novel diagnostic and/or therapeutic targets.