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

Abstract

ABSTRACTCandida 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 (CYR1), the PKA regulatory subunit (BCY1), and the PKA catalytic subunits (TPK1 and TPK2). 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 TPK1 and TPK2 generally resulted in more severe defects than CYR1 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 CYR1 or TPK1/TPK2, which resulted in severe in vitro growth defects at 37°C, did not attenuate virulence, and BCY1 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.