Signaling Pathways Regulating Dimorphism in Medically Relevant Fungal Species

Pathogenic fungi that exhibit the ability to alternate between hyphal and yeast morphology in response to environmental stimuli are considered dimorphic. Under saprobic conditions, some fungi exist as filamentous hyphae, producing conidia. When conidia are inhaled by mammals or traumatically inoculated, body temperature (37 °C) triggers dimorphism into yeast cells. This shift promotes fungal dissemination and immune evasion. Some fungal pathogens undergo dimorphism in the contrary way, forming pseudohyphae and hyphae within the host. While temperature is a major driver of dimorphism, other factors, including CO₂ concentration, pH, nitrogen sources, and quorum-sensing molecules, also contribute to morphological shifts. This morphological transition is associated with increased expression of virulence factors that aid in adhesion, colonization, and immune evasion. Candida albicans is a fungus that is commonly found as a commensal on human mucous membranes but has the potential to be an opportunistic fungal pathogen of immunocompromised patients. C. albicans exhibits a dimorphic change from the yeast form to the hyphal form when it becomes established as a pathogen. In contrast, Histoplasma capsulatum is an environmental dimorphic fungus where human infection begins when conidia or hyphal fragments of the fungus are inhaled into the alveoli, where the dimorphic change to yeast occurs, this being the morphology associated with its pathogenic phase. This review examines the main signaling pathways that have been mostly related to fungal dimorphism, using as a basis the information available in the literature on H. capsulatum and C. albicans because these fungi have been widely studied for the morphological transition from hypha to yeast and from yeast to hypha, respectively. In addition, we have included the reported findings of these signaling pathways associated with the dimorphism of other pathogenic fungi, such as Paracoccidioides brasiliensis, Sporothrix schenckii, Cryptococcus neoformans, and Blastomyces dermatitis. Understanding these pathways is essential for advancing therapeutic approaches against systemic fungal infections.