A possible role for fumagillin in cellular damage during host infection by Aspergillus fumigatus

Abstract

Virulence mechanisms of the pathogenic fungus Aspergillus fumigatus are multifactorial anddepend on the immune state of the host, but little is known about the fungal mechanism thatdevelops during the process of lung invasion. In this study, microarray technology was combinedwith a histopathology evaluation of infected lungs so that the invasion strategy followed by thefungus could be described. To achieve this, an intranasal mice infection was performed to extractdaily fungal samples from the infected lungs over four days post-infection. The pathological studyrevealed a heavy fungal progression throughout the lung, reaching the blood vessels on the thirdday after exposure and causing tissue necrosis. One percent of the fungal genome followed adifferential expression pattern during this process. Strikingly, most of the genes of the intertwinedfumagillin/pseurotin biosynthetic gene cluster were upregulated as were genes encoding lyticenzymes such as lipases, proteases (DppIV, DppV, Asp f 1 or Asp f 5) and chitinase (chiB1) as wellas three genes related with pyomelanin biosynthesis process. Furthermore, we demonstrate thatfumagillin is produced in an in vitro pneumocyte cell line infection model and that loss offumagillin synthesis reduces epithelial cell damage. These results suggest that fumagillin con-tributes to tissue damage during invasive aspergillosis. Therefore, it is probable that A. fumigatusprogresses through the lungs via the production of the mycotoxin fumagillin combined with thesecretion of lytic enzymes that allow fungal growth, angioinvasion and the disruption of the lungparenchymal structure.