The structural language of fungal cell wall sugars in WHO priority fungi: the determinant of pathogenicity and the gateway to new therapies

Abstract

Carbohydrates, far beyond their nutritional role, are fundamental biomolecules that encode biological information and mediate critical cellular interactions. In pathogenic fungi, cell wall (CW) glycans serve as both a protective armor and a dynamic interface with the host, directly influencing virulence and immune evasion. This review discusses the intricate architecture and composition of the CW in the four WHO-critical priority fungal pathogens: Aspergillus fumigatus, Candidozyma auris, Cryptococcus neoformans, and Candida albicans. We detail how distinct carbohydrate polymers, including α- and β-glucans, and various mannans, are organized into layered structures that confer mechanical stability, modulate physicochemical properties, and display pathogen-associated molecular patterns (PAMPs). The analysis highlights species-specific adaptations: the conidial “invisibility cloak” and galactosaminogalactan layer of A. fumigatus; the polymorphic mannoprotein outer layer of C. albicans; the unique polysaccharide capsule anchored to the CW in C. neoformans; and the distinct mannan side chains conferring clade-specific traits in C. auris. Given its essentiality and absence in host cells, the fungal CW presents an ideal target for therapeutic intervention. A deep understanding of the biochemical properties and structural complexity of fungal carbohydrates provides critical insights into novel targets for therapeutic intervention, thereby contributing to the rational design of next-generation antifungals and also aiding the development of new therapies through artificial intelligence.