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

Facts Physiological carbon dioxide (CO 2 ) levels function as a key environmental cue that allows fungal pathogens to sense and adapt to host conditions, coordinating metabolic and developmental responses. CO 2 modulates morphogenesis, biofilm formation, capsule production and developmental pathways, directly contributing to fungal pathogenicity and persistence in host tissues. CO 2 -induced alterations in membrane composition, metabolism and stress pathways can influence antifungal susceptibility and tolerance across different species. These regulatory effects are observed in diverse clinically important fungi, highlighting CO 2 as a conserved and versatile modulator of fungal biology. Insights into CO 2 signaling provide a more physiologically relevant framework for predicting antifungal efficacy and optimizing therapeutic strategies. Open Questions What is the impact of dynamic CO 2 gradients within host-associated niches on fungal virulence, fitness and treatment outcomes? How does CO 2 signaling interact with other environmental cues (e.g., pH, oxygen availability, nutrient status, and microbiota-derived factors) to regulate pathogenicity? To what extent can CO 2 -responsive pathways be safely and effectively exploited as antifungal targets in vivo ? 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.