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 and depend on the immune state of the host, but little is known about the fungal mechanism that develops during the process of lung invasion. In this study, microarray technology was combined with a histopathology evaluation of infected lungs so that the invasion strategy followed by the fungus could be described. To achieve this, an intranasal mice infection was performed to extract daily fungal samples from the infected lungs over four days post-infection. The pathological study revealed a heavy fungal progression throughout the lung, reaching the blood vessels on the third day after exposure and causing tissue necrosis. One percent of the fungal genome followed a differential expression pattern during this process. Strikingly, most of the genes of the intertwined fumagillin/pseurotin biosynthetic gene cluster were upregulated as were genes encoding lytic enzymes such as lipases, proteases (DppIV, DppV, Asp f 1 or Asp f 5) and chitinase (chiB1) as well as three genes related with pyomelanin biosynthesis process. Furthermore, we demonstrate that fumagillin is produced in an in vitro pneumocyte cell line infection model and that loss of fumagillin synthesis reduces epithelial cell damage. These results suggest that fumagillin contributes to tissue damage during invasive aspergillosis. Therefore, it is probable that A. fumigatus progresses through the lungs via the production of the mycotoxin fumagillin combined with the secretion of lytic enzymes that allow fungal growth, angioinvasion and the disruption of the lung parenchymal structure.

In vitro study on aspects of molecular mechanisms underlying invasive aspergillosis caused by gliotoxin and fumagillin, alone and in combination

“…GT is identified to be highly cytotoxic to renal epithelial cells at low concentration and type II epithelial cells at high concentration. It is already known in an in vivo model that GT is a virulence factor and FUM is a likely factor in cellular damage during infection of the host by A. fumigatus 14,53 . This is further substantiated by the down-regulation of cytokines that are generally involved in the regulation of immune system as well as in the control of the fungal pathogenesis.…”

“…Fumagillin (FUM) is a cyclohexane derivative, and identified as a potent angiogenesis inhibitor that reduces the proliferation of endothelial cells for blood vessel formation to avoid infiltration of host’s immune cells to the site of infection 14 . Further, FUM is also involved in IA during hyphal invasion and thereby damage the epithelial layer, inhibit neutrophils and slow down beating of cilia of ciliated epithelial cells 14 – 17 . In fact, A. fumigatus produces both GT and FUM during the early stages of IA, within 30 to 72 h 14 , 15 .…”

“…Further, FUM is also involved in IA during hyphal invasion and thereby damage the epithelial layer, inhibit neutrophils and slow down beating of cilia of ciliated epithelial cells 14 – 17 . In fact, A. fumigatus produces both GT and FUM during the early stages of IA, within 30 to 72 h 14 , 15 . This may facilitate the fungus escape the immune surveillance and propagate the disease so as to become invasive.…”

Fumagillin, a Mycotoxin of Aspergillus fumigatus: Biosynthesis, Biological Activities, Detection, and Applications

“…Finally, the host immune response during colonization/infection and the antifungal treatment employed can also activate these secondary metabolism regulators. The activation of the fumagillin cluster during experimental animal infections has been detected, contributing to the invasion and generation of cell damage [40]. Other authors have shown that, in contact with caspofungin, fumagillin [87] and gliotoxin [88] are overexpressed.…”

“…On the other hand, fumagillin has anti-angiogenic activity [29], probably because of its inhibitory activity against the MetAP2 enzyme; consequently, it has valuable pharmaceutical potential and a potential role in the treatment of cancer [30]. Moreover, this toxin is able to inhibit the function of neutrophils [38], inducing cell death in erythrocytes [39] and plays a role in damaging lung epithelial cells which opens the way to fungal invasion [40], perhaps owing to its antiangiogenic properties.…”