Research Project
10316508
Aspergillus fumigatus is an opportunistic mold that causes difficult to treat invasive fungal infections in immunocompromised and immunosuppressed individuals, often resulting in a lethal outcome. The objective of this competitive renewal R01 is to build upon our recent work that has uncovered roles for bioactive lipid mediators in immune responses during lung fungal infection with A. fumigatus. In the previous funding period, we made three novel findings: (i) IL-33 receptor signaling negatively regulated immunoprotective type 17 responses during A. fumigatus infection, (ii) the eicosanoid PGE2 positively regulated IL-17A and IL-22 induction and (3) IL-33 receptor signaling negatively regulated PGE2 production (J Immunol 99:2140-2148, 2017). In other work supported by this proposal, we reported that deficiency in 12/15-lipoxygenase (12/15-LOX, Alox15-/-) resulted in impaired inflammatory responses and profound susceptibility to lung infection with A. fumigatus (J Immunol 204:1849-1858, 2020). Intriguingly, a mechanism of susceptibility we observed in Alox15-/- mice was impaired neutrophil maturation in the bone marrow. Our findings overall have prompted some interesting questions: (i) how does IL-33 modulate PGE2 during lung fungal infection? (ii) does IL-33 regulate the production of other bioactive lipids? (iii) can bioactive lipids other than PGE2 modulate immune responses during infection with A. fumigatus? (iv) are specific bioactive lipids required for or negatively regulate neutrophil maturation during infection? Lipidomic analysis of lung tissue from A. fumigatus exposed mice demonstrates that IL-33 signaling is a profound negative regulator of multiple bioactive lipid classes, including prostaglandins, hydroxydocosahexaenoic acids (HDHAs), hydroxyeicosapentaenoic acids (HEPEs) and hydroxyeicosatetraenoic acids (HETEs). Data further shows the Alox15-/- mice have a unique lung lipid signature during A. fumigatus infection, one that may function to modulate neutrophil-mediated immunity to A. fumigatus. In other studies, employing Il33flox/flox-eGFP reporter mice and a combination of flow cytometry and fluorescent immunohistochemistry, we show that dendritic cells and neutrophils are immune cell sources of IL-33 whereas alveolar type II cells are the primary non-immune cell source of IL-33 in the lung during A. fumigatus infection. Recent studies suggest that the cellular source of IL-33 (i.e. myeloid vs. epithelial) may have a dramatic effect on the type of immune response. Overall, our hypothesis is that bioactive lipids, regulated by cytokines such as IL-33 and enzymes such as 12/15/-LOX, tune the inflammatory response during A. fumigatus lung infection. The specific aims of the proposal are: (1) to determine the mechanism(s) associated with and function of IL-33 and 12/15-LOX-mediated regulation of bioactive lipids during lung fungal infection and (2) to determine how the cellular source of IL-33 modulates bioactive lipid production and immunity during lung fungal infection.
