Candida immunity · The role of intestinal antigen-presenting cells in generating T cell-mediated antifungal immunity

Intestinal fungi are an important component of the microbiome and their homeostasis/dysbiosis constantly shapes the immune responses. The human commensal fungus Candida albicans colonizes the gut of 40-80% of individuals. However, life-threatening infections caused by this fungus are relatively rare since the unwinding of its pathogenic potential is kept in check by the immune system. In line with this, immunodeficient patients suffer often from Candidiasis, which is typically difficult to treat. Candida albicans induce strong Th17 response which is the main protective mechanism against pathogenic fungi. Candida-induced Th17 cells can protect the host not only against other fungal but also against extracellular pathogens. Besides the positive effects of Th17 in defence against pathogens, recent studies connect fungi-elicited Th17 response with local and gut-distal pathologies such as asthma, multiple sclerosis, Crohn’s disease, or rheumatoid arthritis. Despite that the role of Th17 is relatively well studied, the early events at the initiation of innate and adaptive immune responses against intestinal fungi are much less known. Various mutations in the adaptive immune system are clearly associated with impaired antifungal immunity. The proposed project will fill this knowledge gap by systematic studies of antigen-presenting cells involved in initiating Th17 response upon Candida colonization. We propose to use single-cell RNA sequencing techniques to determine Candida responsive populations followed by deletion of MHCII on selected APCs populations to prove that the effect is mediated via antigen presentation. We will further study the bidirectional interaction between Candida and APCs in these mice. This study will lead to the understanding of events at the beginning of antifungal response via the identification of cell type(s) responsible for Th17 induction as well as the regulation of fungal homeostasis and control of Candida virulence.