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Characterization of a 5-azacytidine-induced developmental Aspergillus fumigatus variant

Ronen Ben-Ami1, Varga Varga, Russell E Lewis

  • 1Department of Infectious Diseases, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Virulence
|December 24, 2010
PubMed

Insights

The hypomethylating agent 5-azacytidine (5AC) can alter Aspergillus fumigatus development and virulence. This study reveals 5AC-induced variants retain full virulence and exhibit increased angioinvasion.

Area of Science:

  • Medical Mycology
  • Molecular Biology
  • Pathogenesis

Background:

  • 5-azacytidine (5AC) is a hypomethylating agent used in patients susceptible to invasive fungal infections.
  • Aspergillus fumigatus is an opportunistic fungal pathogen causing invasive aspergillosis.

Purpose of the Study:

  • To investigate the impact of 5AC on Aspergillus fumigatus developmental competence and virulence.
  • To characterize the phenotypic and pathobiologic changes in 5AC-induced A. fumigatus variants.

Main Methods:

  • Incubation of A. fumigatus strain 293 with 5AC to induce variants.
  • Phenotypic analysis of conidiation and light-dependent rescue.
  • Transcriptional profiling to identify differentially expressed genes.
  • Virulence assessment in Drosophila melanogaster and murine models of invasive aspergillosis.
  • Enzyme activity assays and assessment of angioinvasion.

Main Results:

  • 5AC treatment induced a high-frequency conversion to a fluffy variant (Af293 (FL)) with a conidiation defect, partially rescued by light exposure.
  • Transcriptional profiling indicated differential gene expression in G-protein signaling, including an opsin, suggesting a role for light-responsive pathways.
  • The Af293 (FL) variant demonstrated full virulence in established infection models.
  • Af293 (FL) exhibited overexpression of aspergillopepsin F, increased elastase activity, and enhanced angioinvasion compared to the wild-type strain.

Conclusions:

  • 5-azacytidine can induce significant alterations in Aspergillus fumigatus development and virulence.
  • The 5AC-induced variant highlights the potential for chemotherapeutic agents to modify fungal pathobiology.
  • Understanding these drug-induced changes is crucial for managing opportunistic fungal infections in immunocompromised patients.

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