α-1,3-Glucan-Driven Remodeling of the Conidial Cell Wall in an Aspergillus fumigatus Vaccine Strain Alters Innate Immune Recognition

Abstract

Aspergillus fumigatus is a major cause of invasive aspergillosis in immunocompromised patients, where current antifungal therapies are limited by toxicity, drug resistance, and lack of durable protection, and no vaccines are available. A mutant lacking the sterylglucosidase-encoding gene (sglA) has emerged as a candidate that induces protective immune responses, but the structural basis for this phenotype remains unclear. Here, we use cellular solid-state NMR spectroscopy to compare the organization of the conidial cell wall in {Delta}sglA and its wild-type counterpart. The {Delta}sglA conidial cell wall displays extensive remodeling, including increased -1,3-glucan content and structural polymorphism, strengthened interactions with {beta}-glucans, reduced hydration, and restricted molecular motion, together consolidating a more rigid scaffold with limited {beta}-glucan accessibility. These structural changes are associated with altered neutrophil responses and a shift in innate immune signaling. This work links cell-wall reorganization to altered immune recognition in this vaccine candidate, with implications for future immunotherapeutic strategies. TEASERMolecular-level Insights from a fungal vaccine candidate show how cell-wall remodeling could affect immune response.