Blocking Polyphosphate Mobilization Inhibits Pho4 Activation and Virulence in the Pathogen Candida albicans

Area of Science:

• Mycology and Pathogenesis
• Molecular and Cellular Biology
• Biochemistry

Background:

• Pathogenic fungi require nutrient acquisition for virulence.
• Candida albicans utilizes the Pho4 transcription factor for phosphate acquisition, crucial for virulence and stress resistance.
• Polyphosphate (polyP) serves as an intracellular phosphate store, rapidly mobilized during phosphate starvation.

Purpose of the Study:

• To investigate the role of polyP mobilization in the pathobiology of Candida albicans.
• To identify the key enzymes responsible for polyP mobilization in C. albicans.
• To determine the impact of impaired polyP mobilization on fungal virulence and host-pathogen interactions.

Main Methods:

• Genetic deletion of the Ppn1 and Ppx1 polyphosphatases in C. albicans.
• Analysis of Pho4 transcription factor activation and target gene expression under phosphate-limiting conditions.
• Assessment of stress resistance, DNA replication fidelity, and morphological changes in mutant strains.
• Evaluation of fungal virulence in a relevant host model.

Main Results:

• Ppn1 and Ppx1 function redundantly in polyP mobilization in C. albicans.
• Blocking polyP mobilization prevents Pho4 activation, leading to impaired phosphate acquisition and reduced stress resistance.
• Cells lacking polyphosphatases exhibit sensitivity to DNA replication stress and display significant morphological defects, including resistance to hyphal formation.
• Impaired polyP mobilization significantly attenuates the virulence of C. albicans.

Conclusions:

• PolyP mobilization is essential for Candida albicans virulence by regulating phosphate homeostasis, stress response, and morphogenesis.
• The study identifies Ppn1 and Ppx1 as key players in polyP mobilization, impacting Pho4 activation and critical cellular processes.
• Targeting polyP mobilization presents a promising strategy for developing novel antifungal therapies due to differing phosphate homeostasis mechanisms between fungi and hosts.