Insights into Aspergillus fumigatus morphogenesis and pathogenesis through the putative lipid transporter ArvA.

UNLABELLED: Aspergillus fumigatus poses a significant threat to human well-being, in part due to the increasing emergence of strains resistant to frontline antifungal therapy. In this study, we observed that the gene arvA is required for A. fumigatus morphogenesis, antifungal drug susceptibility, and cell wall homeostasis. Intriguingly, our study reveals novel morphological and growth aberrations in the absence of arvA. Loss of arvA results in hyper-swollen conidia that give rise to stunted, polarity-deficient hyphae in numerous environmental conditions, indicating a pivotal role for arvA in A. fumigatus morphogenesis. Surprisingly, despite these severe in vitro morphological and cell wall defects, arvA was not required for morbidity and mortality in immunologically distinct murine models of invasive pulmonary aspergillosis. However, the mechanisms by which the arvA mutant can cause disease differ between the two models. Growth in natural calf lung surfactant was able to somewhat normalize ∆arvA growth with the wild-type strain, suggesting lung surfactant may partially complement the severe in vitro morphological defects of arvA loss in vivo. Taken together, our observations reveal arvA as a mediator of A. fumigatus antifungal drug susceptibility and highlight the complex and ill-defined pulmonary nutrient environment's role in mediating A. fumigatus pathogenesis and disease progression.

IMPORTANCE

Aspergillus fumigatus is a challenging fungal pathogen in the clinic, in part due to increasing azole drug resistance. In this study, we observed that the loss of the A. fumigatus gene arvA results in increased azole susceptibility and significant in vitro morphological changes highlighted by hyper-swollen conidia that yield stunted and polarity-deficient hyphae. Importantly, despite these severe in vitro morphological and growth abnormalities, ∆arvA surprisingly retains full pathogenicity and virulence in two immunologically distinct murine models of invasive pulmonary aspergillosis. These results challenge our understanding of the in-host environment and how it mediates fungal morphogenesis and pathogenesis. These results, consequently, not only enhance our understanding of the role of arvA in A. fumigatus morphogenesis and drug susceptibility but also further emphasize the importance of in vivo animal models in fully evaluating potential antifungal drug targets.