CO(2) enhances the formation, nutrient scavenging and drug resistance properties of C. albicans biofilms

C. albicans is the predominant human fungal pathogen and frequently colonises medical devices, such as voice prostheses, as a biofilm. It is a dimorphic yeast that can switch between yeast and hyphal forms in response to environmental cues, a property that is essential during biofilm establishment and maturation. One such cue is the elevation of CO(2) levels, as observed in exhaled breath for example. However, despite the clear medical relevance, the effect of CO(2) on C. albicans biofilm growth has not been investigated to date. Here we show that physiologically relevant CO(2) elevation enhances each stage of the C. albicans biofilm-forming process: from attachment through maturation to dispersion. The effects of CO(2) are mediated via the Ras/cAMP/PKA signalling pathway and the central biofilm regulators Efg1, Brg1, Bcr1 and Ndt80. Biofilms grown under elevated CO(2) conditions also exhibit increased azole resistance, increased Sef1-dependent iron scavenging and enhanced glucose uptake to support their rapid growth. These findings suggest that C. albicans has evolved to utilise the CO(2) signal to promote biofilm formation within the host. We investigate the possibility of targeting CO(2)-activated processes and propose 2-deoxyglucose as a drug that may be repurposed to prevent C. albicans biofilm formation on medical airway management implants. We thus characterise the mechanisms by which CO(2) promotes C. albicans biofilm formation and suggest new approaches for future preventative strategies.