Oxidative stress-responsive cell wall remodeling depends on phosphate in Candida albicans

Abstract The growing number of patients susceptible to invasive Candida albicans infections has intensified the need for effective antifungal targets in pathways essential for fungal growth and pathogenesis. Among these pathways, phosphate homeostasis has emerged as a significant determinant of virulence, yet how phosphate availability shapes cell wall structure in response to host-derived oxidative stress remains unclear. During commensal growth, C. albicans cells typically enjoy phosphate repletion and a neutral redox environment. Transitioning to invade host tissues, they simultaneously experience phosphate deprivation and intense extrinsic oxidative stress. Here, we employ solid-state NMR to render details of cell wall remodeling in response to oxidative stress, in its dependence on phosphate. Phosphate deprived cells remodel the rigid wall core and reduce hydration and polymer mobility in the absence of oxidative stress. During hydrogen peroxide exposure, highly mobile outer polysaccharides are primary interactors. In wildtype cells, some of these polymers are recruited into the rigid core, reinforcing the wall scaffold, whereas phosphate transport mutants fail to undergo this remodeling. These findings establish phosphate acquisition as a component of oxidative defense and link nutrient sensing and -availability to the mechanical resilience of the fungal cell wall, revealing an architectural vulnerability with relevance for antifungal development.