P4-ATPase Drs2 regulates virulence, stress adaptation, and autophagy in Candida glabrata

Area of Science:

• Mycology
• Molecular Biology
• Pathogenesis

Background:

• Candida glabrata is an opportunistic fungal pathogen with significant clinical relevance due to its inherent resistance to antifungal drugs.
• Understanding the molecular mechanisms underlying C. glabrata's pathogenicity and stress adaptation is critical for developing effective treatments.

Purpose of the Study:

• To investigate the role of the phospholipid flippase Drs2 (P4-ATPase) in the virulence and stress adaptation of Candida glabrata.
• To identify the molecular pathways regulated by Drs2 in C. glabrata.

Main Methods:

• Construction and characterization of a DRS2 deletion mutant in C. glabrata.
• Assessment of fungal growth, drug susceptibility, stress responses (oxidative stress, autophagy), and virulence in macrophage and Galleria mellonella models.
• Analysis of biofilm formation and metabolic flexibility.
• Transcriptomic profiling to identify Drs2-regulated pathways.

Main Results:

• The DRS2 deletion mutant displayed impaired growth, increased susceptibility to antifungal drugs, and defects in oxidative stress tolerance and autophagy.
• The mutant exhibited reduced survival within macrophages, enhanced pro-inflammatory cytokine production, and attenuated virulence in the Galleria mellonella model.
• Drs2 deficiency led to diminished biofilm formation and impaired metabolic flexibility under nutrient limitation.
• Transcriptomic analysis revealed Drs2 as a regulator of MAPK signaling, cell wall integrity, and oxidative stress response pathways.

Conclusions:

• Drs2 is essential for maintaining membrane homeostasis, linking cellular stress adaptation to virulence in Candida glabrata.
• Drs2 plays a critical role in fungal pathogenicity, stress tolerance, and metabolic flexibility.
• Drs2 represents a promising therapeutic target for combating drug-resistant Candida glabrata infections.