Host-mimicking hypoxic conditions reveal <i>EPA6</i> -dependent adhesion and dissemination of <i>Candida glabrata</i>

Candida glabrata is a major fungal pathogen capable of causing life-threatening disseminated infections, especially in immunocompromised individuals. Oxygen levels vary widely across host niches, and hypoxia is increasingly recognized as a key modulator of fungal pathogenicity. However, how low-oxygen environments influence adhesion and virulence in C. glabrata remains poorly understood. Here, we investigated C. glabrata adhesion under rigorously controlled oxygen conditions using a sealed hypoxic workstation and identified genes responsible for hypoxia-induced adhesion. Adhesion to human epithelial and endothelial cells was significantly enhanced under hypoxic conditions. RNA-seq analysis revealed that among differentially expressed genes, the adhesin gene EPA6 was consistently upregulated under anaerobic conditions in multiple strains. Using gene deletion and complementation, we found that EPA6 is required for adhesion under hypoxia. Using three distinct in vivo models (intravenous infection, gastrointestinal colonization, and systemic dissemination from the gut), we showed that EPA6 was crucial for fungal burden and pathogenicity. Because the epa6Δ mutant had normal growth and stress tolerance, we consider that its attenuated virulence (reduced colonization and dissemination) resulted from reduced adhesion. This study provides the first demonstration of fungal adhesion under precisely monitored oxygen conditions that mimic those in host physiology. These findings demonstrate that hypoxia promotes C. glabrata adhesion and dissemination through EPA6, highlighting a key virulence mechanism.