Statement of Purpose: Fungi have long been associated with asthmatic diseases, yet the exact mechanism(s) by which fungi induce asthma is unknown. We propose that fungal lipoxygenase enzymes and their eicosanoid products are involved in asthmatic diseases. Human 5-lipoxygenase derived leukotrienes induce inflammation, mucus secretion, vasodilation, and bronchial constriction. We hypothesize that the fungal pathogen Aspergillus fumigatus is capable of secreting a 5-lipoxygenase homolog, LoxB, that participates in eicosanoid production, including leukotrienes. This secreted homolog is translocated into lung epithelial cells, participates in the production of leukotriene and other eicosanoids, and exacerbates asthmatic responses, such as bronchoconstriction. Together, this work will help delineate the role fungal products play in asthmatic diseases. Methods:We are assessing fungal interactions with lung epithelial cells using a microfluidic in-vitro platform followed by murine asthma model research. To assess the effects of LoxB overexpression, mass spectrometry was used to identify eicosanoid oxylipins within culture supernatants. Results: We have identified an Aspergillus fumigatus lipoxygenase, LoxB, with high identity to human 5-lipoxygenase. Moreover, we have identified a motif in LoxB that may mediate entry into lung epithelial cells. To fully understand the impact of LoxB in asthma, we have developed an Aspergillus fumigatus strain that overexpresses LoxB. Overexpression of LoxB results in increased levels of various eicosanoids that are known to cause airway hyperresponsiveness and increased mucus production. Future work will focus on characterizing the effect these eicosanoid products have on the airway and whether fungal effector translocation result in increased leukotriene levels.
Full conference title:
27th Fungal Genetics Conference
- Fungal Genetics Conference 27th (2013)