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Related Experiment Videos

Molecular genetics of Aspergillus pathogenicity

D W Holden1, C M Tang, J M Smith

  • 1Department of Infectious Diseases and Bacteriology, Royal Postgraduate Medical School, Hammersmith Hospital, London, UK.

Antonie Van Leeuwenhoek
|January 1, 1994
PubMed
Summary

Extracellular elastase and restrictocin from Aspergillus fumigatus do not significantly impact invasive pulmonary aspergillosis (IPA) virulence. However, p-aminobenzoic acid biosynthesis is essential for fungal growth in the lung, indicating a potential drug target.

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Area of Science:

  • Mycology
  • Infectious Diseases
  • Medical Microbiology

Background:

  • Aspergillus fumigatus is a primary cause of Invasive Pulmonary Aspergillosis (IPA), a severe lung infection in immunocompromised individuals.
  • Extracellular virulence factors like elastase and toxins are hypothesized to aid fungal growth in lung tissue.

Purpose of the Study:

  • To investigate the role of extracellular alkaline protease with elastase activity (AFAlp) and restrictocin in the virulence of Aspergillus fumigatus during IPA.
  • To identify essential fungal metabolic genes required for growth in the lung as potential antifungal drug targets.

Main Methods:

  • Generation of Aspergillus fumigatus null mutant strains lacking AFAlp or restrictocin using gene disruption.
  • Comparison of virulence and histopathology of mutant strains versus the parental strain in murine models of IPA (steroid-treated and neutropenic mice).

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  • Establishment of a murine IPA model using Aspergillus nidulans with auxotrophic mutations (lysA2, pabaA1) to study metabolic pathway requirements.

    • Main Results:

    • No significant differences in virulence or histopathology were observed between wild-type and mutant strains lacking AFAlp or restrictocin, indicating these proteins are not critical independent virulence factors.
    • Lysine biosynthesis (lysA2) was not essential for pulmonary disease development in the Aspergillus nidulans model.
    • p-aminobenzoic acid (PABA) biosynthesis (pabaA1) was found to be essential for fungal growth and pathogenicity in the murine lung.

    Conclusions:

    • Independently, extracellular elastase (AFAlp) and restrictocin are not major determinants of Aspergillus fumigatus virulence in IPA.
    • p-aminobenzoic acid biosynthesis is a critical metabolic pathway for fungal survival and growth within the lung environment.
    • The pabaA gene in Aspergillus fumigatus represents a promising target for the development of novel antifungal therapies.