Calcium transport systems as virulence determinants: Mechanistic insights into fungal pathogenicity and antifungal resistance

This review examines the molecular mechanisms through which calcium transport proteins modulate virulence and drug resistance in human pathogenic fungi, synthesizing recent advances in calcium homeostasis research. Emerging evidence from calcium signaling pathway analyses reveals that fungal calcium transporters (including PMC1, VCX1, and CCH1/MID1 complexes) orchestrate critical stress adaptation processes through calcineurin-dependent and calcineurin-independent pathways, highlighting their critical involvement in fungal physiology, adaptive stress responses, and pathogenicity. Through a systematic evaluation of genetic, biochemical, and clinical studies, we elucidate how these transport systems mediate fungal cell wall integrity, biofilm formation, and efflux pump regulation, which are key determinants of virulence evolution and the development of azole resistance. The mechanistic framework presented not only advances our understanding of calcium-mediated fungal pathogenesis but also identifies these transport systems as promising targets for antifungal development, particularly for overcoming multidrug resistance in Candida, Cryptococcus and Aspergillus species.