Sensing the host atmosphere: carbon dioxide regulates virulence and drug response in medically relevant fungi

Carbon dioxide (CO 2 ) is a pivotal environmental signal that influences the physiology, development and pathogenic potential of fungi. Beyond its role as a metabolic by-product, CO 2 functions as a conserved signaling molecule that enables fungal pathogens to sense and adapt to host niches. This review synthesizes current knowledge on how fluctuations in CO 2 concentration modulate growth dynamics, morphogenesis, virulence-associated attributes and antifungal susceptibility in clinically important yeasts and filamentous fungi. In Candida species, particularly Candida albicans , physiological CO 2 levels encountered in host tissues (~5%) act as a potent morphogenetic signal, driving the yeast-to-hypha transition, promoting biofilm formation and inducing metabolic reprogramming; processes tightly linked to tissue invasion and persistence. CO 2 exposure also alters membrane composition and stress response pathways, thereby modulating susceptibility to antifungal agents. In Cryptococcus neoformans , elevated CO 2 concentrations promote capsule biosynthesis and enlargement, alongside extensive remodeling of surface architecture and membrane composition. These CO 2 -driven adaptations strengthen resistance to host immune defenses and are associated with increased tolerance to antifungals. In Aspergillus species, CO 2 availability influences growth, mycotoxin biosynthesis and developmental trajectories by shifting the balance between asexual and sexual reproduction, with downstream effects on virulence and antifungal responsiveness. In Scedosporium / Lomentospora species, CO 2 promotes conidial germination and developmental transitions that may indirectly impact antifungal susceptibility and pathogenic fitness. Collectively, these findings highlight environmental CO 2 as a pivotal and dynamic regulator of fungal biology, offering key insights into host-pathogen interactions, informing the prediction of antifungal susceptibility profiles and supporting the rational optimization of therapeutic strategies in clinical settings.