Candida albicans is a human commensal microorganism that can cause life-threatening systemic infections in immunocompromised individuals. A significant virulence trait of C. albicans is its ability to undergo transition between yeast and hyphal (filamentous) morphologies. The hyphal switch allows effective invasion of host tissues, and confers the ability to form biofilms and to block an adaptive immune response. Thus the suppression of hyphal morphogenesis is of both fundamental and therapeutic importance.
In a screen for kinases able to suppress hyphal morphogenesis, we identified Akl1, whose homolog in baker’s yeast is involved in the regulation of endocytosis. We find that CaAkl1 overexpression suppresses fluid phase endocytosis as well as hyphal morphogenesis, whereas deletion of this gene has a stimulatory effect on both processes.
In a related screen, using libraries of compounds that either serve as drugs or have undergone clinical trials (“repurposing screen”), we identified two molecules out of over 3000 screened that suppress hyphal morphogenesis. Using strains that allow ectopic activation of hyphal morphogenesis at different stages along the induction pathway, one of these, Trifluoperazine, was found to exert it effect mainly within, or downstream of, the MAP kinase pathway. Trifluoperazine exposure also resulted in a reduction of biofilm formation. Using different C. albicans and S. cerevisiae genomic library screens, we identified candidate genes for the sites of action for hyphal morphogenesis-suppressing drugs. Many of these genes are involved in endocytosis. Our results thus highlight the little-studied role of endocytosis in hyphal morphogenesis.
