Aspergillus fumigatus and Cryptic Species Exhibit Distinct Strategies for Adaptation to Host-Relevant Conditions

We investigated whether divergence in virulence-associated proteins accompanies phenotypic diversification across section <i>Fumigati</i>. Forty virulence-associated proteins were analyzed across 71 genomes, while 16 random representative isolates were evaluated under host-relevant conditions.

Protein-based multidimensional scaling revealed species-specific divergence in virulence-associated proteins, most prominently for host interactions, and secondary metabolism.</p><p dir="ltr">Phenotype-based principal component analysis reproduced the species-level clustering observed in protein-based analyses, separating <i>A. fumigatus</i> from cryptic species. Cryptic species displayed enhanced metabolic activity and biomass production on alternative respiratory carbon sources, reduced macrophage damage, and higher frequency of pan-azole resistance. <i>A. fumigatus</i> exhibited faster germination, greater metabolic activity and biomass under thermal, osmotic, cell wall and oxidative stress, and enhanced fungal persistence following macrophage interaction.