Adenylyl Cyclase and Protein Kinase A Play Redundant and Distinct Roles in Growth, Differentiation, Antifungal Drug Resistance, and Pathogenicity of Candida auris

Candida auris is a globally emerging multidrug-resistant fungal pathogen. Its pathogenicity-related signaling networks are largely unknown. Here, we characterized the pathobiological functions of the cyclic AMP (cAMP)/protein kinase A (PKA) signaling pathway in C. auris. We focused on adenylyl cyclase ( ), the PKA regulatory subunit ( ), and the PKA catalytic subunits ( and ). We concluded that PKA acts both dependently and independently of Cyr1 in C. auris. Tpk1 and Tpk2 have major and minor roles, respectively, in PKA activity and functions. Both Cyr1 and PKA promote growth, thermotolerance, filamentous growth, and resistance to stress and antifungal drugs by regulating expression of multiple effector genes. In addition, Cyr1 and PKA subunits were involved in disinfectant resistance of C. auris. However, deletion of both and generally resulted in more severe defects than deletion, indicating that Cyr1 and PKA play redundant and distinct roles. Notably, Tpk1 and Tpk2 have redundant but Cyr1-independent roles in haploid-to-diploid cell transition, which increases virulence of C. auris. However, Tpk1 and Tpk2 often play opposing roles in formation of biofilms and the cell wall components chitin and chitosan. Surprisingly, deletion of or , which resulted in severe growth defects at 37°C, did not attenuate virulence, and deletion reduced virulence of C. auris in a systemic murine infection model. In conclusion, this study provides comprehensive insights into the role of the cAMP/PKA pathway in drug resistance and pathogenicity of C. auris and suggests a potential therapeutic option for treatment of C. auris mediated candidemia. Despite the recently growing concern of pan-resistant Candida auris infection, the pathogenicity of this ascomycetous fungal pathogen and the signaling circuitries governing its resistance to antifungal drugs are largely unknown. Therefore, we analyzed the pathobiological functions of cyclic AMP (cAMP)/protein kinase A (PKA) signaling pathway in C. auris, which plays conserved roles in the growth and virulence of fungal pathogens. We show that adenylyl cyclase Cyr1 and PKA have pleiotropic roles in growth, morphogenesis, stress responses, antifungal drug and disinfectant resistance, and ploidy shifts of C. auris. Notably, however, we observed that the Δ Δ mutant generally exhibited more disrupted phenotypes than the Δ mutant, and we suggest Tpk1 and Tpk2 have both cAMP-dependent and -independent roles in this pathogen. Most surprisingl