Trypacidin, a spore-borne toxin from Aspergillus fumigatus, is cytotoxic to lung cells

Area of Science:

• Medical Mycology
• Toxicology
• Cell Biology

Background:

• Inhalation of Aspergillus fumigatus spores can lead to severe aspergillosis in immunocompromised individuals.
• A. fumigatus produces airborne secondary metabolites with largely uninvestigated respiratory toxicity.

Purpose of the Study:

• To identify and characterize toxic secondary metabolites from A. fumigatus conidia.
• To investigate the toxicity of these compounds on human lung cells and elucidate the cell death mechanism.

Main Methods:

• Fractionation of A. fumigatus culture extracts using RP-HPLC and LC-MS.
• Purification and structural verification of compounds using NMR.
• Assessment of cytotoxicity on A549 lung cells and human bronchial epithelial cells.
• Analysis of cell death pathways, including oxidative stress markers and apoptosis indicators.

Main Results:

• Five main compounds were identified in A. fumigatus spores: tryptoquivaline F, fumiquinazoline C, questin, monomethylsulochrin, and trypacidin.
• Questin, monomethylsulochrin, and trypacidin exhibited toxicity to A549 lung cells.
• Trypacidin was the most potent toxin, causing cell lysis and decreased viability (IC₅₀ ≈ 7 µM) in lung and bronchial cells.
• Trypacidin induced intracellular nitric oxide and hydrogen peroxide formation, leading to necrotic cell death within 24 hours.
• Apoptosis was not implicated in trypacidin-induced cell death.

Conclusions:

• Trypacidin is a highly toxic secondary metabolite from A. fumigatus that induces necrotic cell death in lung epithelial cells through oxidative stress.
• This study provides the first report on the toxicity of trypacidin to lung cells, highlighting a potential respiratory health risk associated with A. fumigatus spore inhalation.