Interspecies pheromone signaling promotes biofilm formation and same-sex mating in Candida albicans

The opportunistic pathogen Candida albicans undergoes a parasexual mating cycle in which cells must switch from the conventional "white" form to the alternative "opaque" form to become mating competent. Pheromones secreted by opaque cells induce the formation of polarized mating projections and result in cell-cell conjugation. In contrast, white cells are unable to undergo mating, but can still respond to pheromone by expression of adhesion genes that promote biofilm formation. In this study, we have analyzed the dual ability of pheromones to activate mating by opaque cells and biofilm formation by white cells. We first show that there is considerable plasticity in interactions between the a pheromone and its receptor, Ste2, by analysis of analogs of the a pheromone. Significantly, substituted forms of a pheromone can induce a response in opaque cells and this is sufficient to drive same-sex a-a cell fusion and homothallic mating. In addition, pheromone analogs were able to induce adhesion and biofilm formation in white cells of C. albicans. Because of the observed plasticity in pheromone signaling, we subsequently tested putative pheromones from multiple Candida species and identified nonnative ligands that can induce self-mating and biofilm responses in C. albicans. Our findings demonstrate that environmental signals can initiate C. albicans parasexual reproduction and biofilm formation, and highlight the role of the pheromone-signaling apparatus in mediating these functions.