Exposure to the mold Aspergillus fumigatus may result in a range of conditions from one of the worst forms of asthma, allergic bronchopulmonary aspergillosis (ABPA), to one of the most lethal fungal infections known, invasive aspergillosis (IA). We have previously reported a comprehensive role for the beta-glucan receptor Dectin-1 and Dectin-1 mediated IL-22 production in innate immune responses after A. fumigatus exposure. Examining IL-22 cell sources using novel IL-22 reporter mice, we have discovered kinetic production of IL-22 by multiple cell types. We have also discovered that a member of the common ?-chain cytokine family is required for lung IL-22 production whereas specific members of the IL-1/TLR family negatively regulate IL-22. Mechanistically, we have found that this negative regulation of IL-22 is associated with downregulation of COX- 2 mediated pathways that promote IL-22. We have previously reported that IL-22 deficient mice had impaired levels of soluble factors that mediate antifungal immunity. However, we excluded several known IL-22 associated antimicrobial factors as mediators of the IL-22 dependent antifungal response. In a pilot proteomic analysis of lung lavage fluid, we identified the acute phase proteins that mediate antifungal defense via the regulation of iron availability. Together, our proposed studies will identify cell types producing IL-22, what pathways regulate the production of IL-22 and how IL-22 mediates antifungal defense. A better understanding of IL-22 biology will better inform the development of therapeutics to treat the wide range of conditions associated with A. fumigatus exposure.
The specific aims of the proposal are: (1) Identify cell sources of IL-22 and the magnitude by which different common ?-chain cytokines affect the IL-22 response during acute A. fumigatus lung infection, (2) Determine arachidonic acid metabolism pathways promoting lung IL-22 responses during acute A. fumigatus lung infection and whether/how these are regulated by specific IL-1/TLR family members and (3) Identify IL-22 dependent antifungal factors during acute A. fumigatus lung infection.
This proposal seeks to identify cell types in the lung that produce the cytokine IL-22, what pathways positively and negatively regulate the production of IL-22 and how IL-22 mediates antifungal defense in the lung. A better understanding of IL-22 biology will better inform the development of therapeutics to treat the wide range of conditions and the different lung diseases associated with Aspergillus fumigatus exposure.
