Fungal Adenylyl Cyclase Integrates CO2 Sensing with cAMP Signaling and Virulence

Summary The ascomycete Candida albicans is the most common fungal pathogen in immunocompromised patients [1]. Its ability to change morphology, from yeast to filamentous forms, in response to host environmental cues is important for virulence [2–5]. Filamentation is mediated by second messengers such as cyclic adenosine 3′,5′-monophosphate (cAMP) synthesized by adenylyl cyclase [4]. The distantly related basidiomycete Cryptococcus neoformans is an encapsulated yeast that predominantly infects the central nervous system in immunocompromised patients [6–8]. Similar to the morphological change in C. albicans , capsule biosynthesis in C. neoformans , a major virulence attribute, is also dependent upon adenylyl cyclase activity [7]. Here we demonstrate that physiological concentrations of CO 2 /HCO 3 − induce filamentation in C. albicans by direct stimulation of cyclase activity. Furthermore, we show that CO 2 /HCO 3 − equilibration by carbonic anhydrase is essential for pathogenesis of C. albicans in niches where the available CO 2 is limited. We also demonstrate that adenylyl cyclase from C. neoformans is sensitive to physiological concentrations of CO 2 /HCO 3 − . These data demonstrate that the link between cAMP signaling and CO 2 /HCO 3 − sensing is conserved in fungi and reveal CO 2 sensing to be an important mediator of fungal pathogenesis. Novel therapeutic agents could target this pathway at several levels to control fungal infections.