Molecular and regulatory aspects of EPA: a Nakaseomyces glabratus epithelial adhesin.

Nakaseomyces glabratus has been recognized worldwide as a formidable fungal pathogen, mostly associated with healthcare-related infections. It leads to persistent and recurrent infections due to its ability to form biofilms on medical devices and its innate resistance to antifungals. The first step in biofilm formation is the adhesion of fungal cells to the surface. Epithelial adhesins (EPAs), a family of glycosylphosphatidylinositol (GPI)-anchored cell wall proteins, play a central role in mediating adhesion. The EPA genes are located in sub-telomeric regions and are tightly regulated by the Sir silencing complex, epigenetic modifications, and environmental factors such as nicotinic acid limitation. Sub-telomeric silencing ensures phenotypic plasticity. EPA paralogs bind to the host glycans via PA14 domains with calcium-dependent interactions, while hydrophobic interactions facilitate adhesion to abiotic surfaces. Synergistic actions of transcription factors and stress-responsive regulators contribute to EPA-mediated biofilm development. The strain-specific diversity and redundancy in EPA paralogs challenge therapeutic targeting of adhesins. However, like Candida albicans Als3 inhibitors, galactose analogs, Sir2 inhibitors and monoclonal antibodies are a few promising anti-adhesion strategies. This review broadly discusses the molecular and regulatory mechanisms governing EPA function in N. glabratus, its role in biofilm development, and its role in host-pathogen interactions. By elucidating EPA's multifaceted regulation, its therapeutic potential can be understood, paving the way for novel avenues to combat resilient infections.