Virulence and immune evasion: unraveling the evolutionary strategies of Candida species

Candida species cause infections from superficial to life-threatening systemic infections, affecting over a billion people annually. How these fungi became successful opportunistic pathogens is unclear. This thesis investigates Candida evolution in response to diet and environmental pressures, gene family innovations, and fungal and host strategies promoting immune evasion, intracellular persistence, and phagocyte escape. Comparative and experimental evolution showed that C. albicans is not strictly a human commensal. Environmental isolates displayed virulence similar to clinical strains, including an amphotericin B-resistant isolate from a previously unrecognized clade. Long-term evolution of a low-virulence isolate in a sugar-rich, western diet-like medium induced stable adaptations, increasing metabolic flexibility, tissue damage, and multidrug resistance, highlighting diet and environmental reservoirs as drivers of pathogenicity. Analysis of the expanded TLO gene family revealed paralogs with distinct effects on filamentation, biofilm formation, stress tolerance, and epithelial invasion. TLOα1 rescued multiple virulence programs, suggesting paralog-specific regulation creates population heterogeneity that enhances colonization and infection. Host-pathogen studies identified two macrophage evasion strategies. C. albicans rapidly consumes glucose, starving macrophages, triggering NINJ1-mediated membrane rupture, and escapes. C. glabrata uses programmed persistence, with mitophagy and petite cells delaying escape, enhancing intracellular survival and antifungal resistance, regulated by the kinase Ksp1. This work reflects the evolutionary path to pathogenicity by showing how environmental and host-imposed pressures, including diet, drive genomic adaptations in Candida species, such as subtelomeric gene-family expansions enabling novel adaptive strategies. These changes produce phenotypic shifts that increase pathogenic potential or facilitate host exploitation.