Candidalysin promotes fungal-specific Th17 CD4 T cell differentiation and protective systemic immunogenicity

Commensal microbes can cause invasive infection but can also stimulate protective immune responses as exemplified by the gut pathobiont Candida albicans. This species primes systemic Th17 immunogenicity which protects against disseminated infection, and yet the fungal determinants driving protection remain uncertain. Here we show an essential role for the cytolytic toxin candidalysin for C. albicans colonization-induced systemic Th17 immunogenicity and protection against invasive infection. Mice intestinally colonized with candidalysin-deficient cells show reduced accumulation of CD4 T cells with defined fungal specificity, despite similar intestinal colonization levels to wildtype C. albicans cells. Fungal-specific RORγt+ CD4 T cells are particularly reduced together with their production of IL17A and IL17F cytokines, whereas expression of transcription factors and production of cytokines representative of other helper T cell lineages are unaffected. Protection against fungemia conferred by colonization with wildtype C. albicans is overturned in mice colonized with candidalysin-deficient cells as shown by increased fungal pathogen burden and reduced survival after intravenous infection. These results establish the necessity for candidalysin for priming Th17 fungal-specific adaptive immune cells and highlight paradoxical protective roles for this fungal virulence factor for promoting host defense against invasive systemic disease.