Molecular Mechanisms in Aspergillus Pathogenicity

The genus Aspergillus comprises ubiquitous filamentous fungi, of which Aspergillus fumigatus is the pre-eminent opportunistic human pathogen. Pathogenicity arises from a concert of molecular processes that enable spore survival, tissue invasion and immune evasion. Central to virulence are pathways governing cell wall integrity, which coordinate the biosynthesis and remodelling of β-glucans, chitin and galactomannans to withstand host stress. Sterol regulatory element binding proteins (SREBPs) orchestrate ergosterol biosynthesis and permit growth under hypoxic microenvironments encountered in infected tissue. Melanin synthesis and secreted toxins further modulate host phagocyte function and oxidative defences. At the genetic level, high rates of meiotic recombination generate novel allelic combinations—facilitating the rapid emergence of drug-resistant haplotypes—while mitochondrial genotypes interact with ergosterol pathways to influence azole persistence. Transcription factors and chromatin remodellers integrate environmental cues, regulating genes for nutrient acquisition, secondary metabolism and stress adaptation. Understanding these intertwined networks has underpinned the development of combination therapies and novel antifungal targets with global significance for managing invasive aspergillosis.

Research from Nature Portfolio

Recent studies have shown that the host defence peptide mimetic brilacidin profoundly potentiates the echinocandin caspofungin against A. fumigatus by disrupting cell wall integrity signalling and altering membrane potential. In murine models of invasive pulmonary aspergillosis and fungal keratitis, the combination not only enhances fungal clearance but also limits infection in azole-resistant and intrinsic caspofungin-resistant isolates. This approach highlights the promise of adjunctive agents that simultaneously target cell wall biosynthesis and membrane homeostasis to overcome emerging antifungal resistance.

Molecular Mechanisms in Aspergillus Pathogenicity publication trend

The graph below shows the total number of articles in molecular mechanisms in aspergillus pathogenicity across all publications each year (not limited to Nature Index journals).

Technical terms

Cell wall integrity pathway: A conserved mitogen-activated protein kinase cascade that senses cell wall stress and regulates enzymes for polysaccharide synthesis and repair.

Ergosterol: The principal fungal membrane sterol essential for membrane fluidity and the target of azole antifungals.

Mitogenome: The complete set of mitochondrial DNA encoding proteins for oxidative phosphorylation and regulators of metabolic adaptation.

Meiotic crossover: Reciprocal exchange of DNA segments between homologous chromosomes during sexual reproduction, generating genetic diversity.

Azole persistence: A reversible, non-heritable tolerance phenotype allowing fungal cells to survive transient exposure to azole drugs.

References

1. A host defense peptide mimetic, brilacidin, potentiates caspofungin antifungal activity against human pathogenic fungi. Nature Communications (2023).
2. Aspergillus fumigatus—What Makes the Species a Ubiquitous Human Fungal Pathogen?. PLOS Pathogens (2013).
3. A Sterol-Regulatory Element Binding Protein Is Required for Cell Polarity, Hypoxia Adaptation, Azole Drug Resistance, and Virulence in Aspergillus fumigatus. PLOS Pathogens (2008).
4. Aspergillus fumigatus melanins: interference with the host endocytosis pathway and impact on virulence. Frontiers in Microbiology (2013).
5. The Aspergillus fumigatus cell wall integrity signaling pathway: drug target, compensatory pathways, and virulence. Frontiers in Microbiology (2015).
6. Aspergillus fumigatus mitogenomes and their influence on azole-resistant and -susceptible populations. npj Antimicrobials and Resistance (2025).
7. The human fungal pathogen Aspergillus fumigatus can produce the highest known number of meiotic crossovers. PLOS Biology (2023).