The contribution of eosinophils and the IL-23/IL-17 axis to host responses to Aspergillus

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Project Summary/Abstract The spectrum of diseases caused by the opportunistic fungal pathogen, Aspergillus, depends in large measure upon the immune status of the host. Over 5 million people suffer from allergic forms of aspergillosis including allergic bronchopulmonary aspergillosis and severe asthma with fungal sensitization. Eosinophils are hallmarks and drivers of allergic aspergillosis but the mechanisms by which eosinophils contribute to immunopathology are not well understood. On the other end of the spectrum, invasive aspergillosis occurs mostly in severely immunocompromised persons; over 200,000 people annually are afflicted and the mortality rate is high. The contribution of eosinophils to immunity in invasive aspergillosis is uncertain; however, we have observed that mice lacking eosinophils are hypersusceptible. The IL-23/IL17 axis is postulated to play a role in immune responses to Aspergillus species and to contribute to the pathophysiology of some forms of asthma. We have discovered that following pulmonary challenge with live Aspergillus fumigatus conidia or aerosol challenge of sensitized mice with A. fumigatus antigens, lung eosinophils express IL-23 and IL-17. Moreover, mice lacking eosinophils have reduced IL-23 and IL-17 in their lungs following A. fumigatus challenge. The overarching hypotheses of this proposal are: 1) eosinophils are major drivers of the IL-23/IL-17 axis in pulmonary aspergillosis; and 2) eosinophilic production of IL-23 and IL-17 is protective in invasive aspergillosis but detrimental in allergic aspergillosis. Our interrelated specific aims will test these hypotheses. Aim 1 is to determine the drivers and consequences of eosinophil production of IL-23/IL-17 in allergic and invasive aspergillosis. We hypothesize that eosinophil expression of IL-23 and IL-17, driven by signaling through C-type lectin receptors, informs immunological responses and outcome in IPA and APA. Aim 2 is to assess the contribution of IL-23R and RORγt to the phenotype of IL-17+/IL-23+ lung eosinophils elicited in response to live Aspergillus and Aspergillus antigens. We postulate that in the setting of Aspergillus stimulation, eosinophils respond to autocrine IL-23 via the IL-23R which turns on expression of the transcription factor RORγt leading to IL-17 expression. Aim 3 is to elucidate cellular targets of eosinophil IL-23/IL-17 responsible for innate and adaptive immune responses. Mechanistic insights into how eosinophil IL-23 and IL-17 expression informs innate and adaptive immunity to Aspergillus will be garnered as we test the hypothesis that lung epithelial cells and T cells are cellular targets of eosinophil-derived IL-17 and IL-23, respectively. Successful completion of the proposed hypothesis-driven studies will have a large overall impact on our understanding of eosinophil biology, the IL-23/IL-17 axis, and the immunology of invasive and allergic forms of aspergillosis. The project has translational significance as the results could suggest rationales for clinical trials in humans with diseases featuring eosinophil-mediated pathology.