Coordinated GlcNAc transport couples nutrient acquisition to invasive growth and virulence in Candida albicans

Abstract

Candida albicans is a prevalent gut commensal and opportunistic fungal pathogen whose transition from intestinal colonization to invasive infection is influenced by environmental cues. N-acetylglucosamine (GlcNAc), abundant in the gut from host and microbial sources, serves not only as a carbon source but also as a potent signal that promotes hyphal morphogenesis and virulence. However, how C. albicans coordinates GlcNAc uptake to regulate these pathogenic responses remains incompletely understood. Here, we identify Hgt1, a canonical glucose transporter, as an alternative GlcNAc transporter that cooperates with the GlcNAc-specific transporter Ngt1 to promote fungal morphogenesis and virulence. Simultaneous deletion of HGT1 and NGT1 markedly impairs GlcNAc-induced hyphal morphogenesis and virulence-associated gene expression. Mechanistically, Hgt1 facilitates the initial uptake of GlcNAc, promoting Ngt1 induction and subsequent robust hyphal growth, as evidenced by delayed Ngt1 expression and hyphal formation in cells lacking HGT1. These findings reveal a coordinated uptake mechanism involving two differentially regulated sugar transporters that enables C. albicans to respond efficiently to GlcNAc availability. Importantly, disruption of GlcNAc uptake reduces fungal dissemination to distal organs and associated host inflammatory responses in a mouse intestinal colonization model under GlcNAc-supplemented conditions. Together, our findings uncover a previously unrecognized mechanism by which C. albicans coordinates sugar transport to drive nutrient-induced pathogenicity, highlighting GlcNAc uptake as a potential target for limiting fungal virulence and systemic dissemination.