Insights on molecular drivers of phenotypic plasticity in Candidozyma auris.

Candidozyma auris (or Candida auris) is the first fungal species declared as a global health threat by the U.S. Center for Disease Control and Prevention (CDC). Its high environmental persistence, immune evasion, phenotypic heterogeneity, and multidrug resistance are major contributors to its high mortality rate. Under diverse environmental conditions, C. auris exhibits marked phenotypic plasticity, switching from non-aggregative to aggregative form and, in some contexts, pseudohyphal-like morphotypes. However, the significance of this heterogeneity in pathogenesis and drug tolerance remains poorly understood. This review provides a comprehensive overview of how external cues influence C. auris morphotypes, with particular emphasis on aggregation. It further highlights the role of adhesion-associated genes (ALS4112 and SCF1) in mediating cell aggregation and examines their evolutionary trajectories across Candida species and among distinct C. auris clades. In addition, we discuss emerging molecular mechanisms that may underlie differential morphotypes and their links to virulence and antifungal tolerance. Evidence suggests that mannan-mediated masking of pathogen-associated molecular patterns (PAMPs) in the aggregative phenotype may contribute to persistence and reduced virulence in the host. Overall, C. auris can remodel its cell wall and elicit distinct host immune responses based on its form, opening avenues for novel therapeutic strategies which further require deeper experimental validation.