All ETDs from UAB

Advisory Committee Chair

Chad Steele

Advisory Committee Members

David Chaplin

Charles Elson

Robin Lorenz

Lisa Schwiebert

Document Type

Dissertation

Date of Award

2013

Degree Name by School

Doctor of Philosophy (PhD) College of Arts and Sciences

Abstract

Opportunistic fungus Aspergillus fumigatus can cause a wide range of disorders depending on the immunological state of the host. In individuals lacking a robust innate immune response, invasive aspergillosis (IA) within the lungs can occur. In contrast, patients with a hyperreactive immune response can develop an allergic disorder called Allergic Bronchopulmonary Aspergillosis (ABPA). Using mouse models, we investigated contributing factors of host defense in IA and fungal asthma induced by Aspergillus fumigatus. The connection between fungi and the development of allergic disease has long been of interest. Previously, we have shown that beta-glucan receptor, dectin-1, is required for clearance during an invasive A. fumigatus infection. In this study, we show that dectin-1 and dectin-1-dependent IL-22 contribute to immunopathogenesis during chronic A. fumigatus exposure. Dectin-1-deficient mice displayed better lung function post-exposure that correlated with a reduction in pro-inflammatory and pro-allergic mediators in the lung. Assessment of purified CD4+ T cells revealed that Th2 cytokines and IL-17A were produced in a dectin-1-dependent manner. In contrast, Th17-related cytokine IL-22 was produced in a dectin-1-dependent manner in unfractionated lung cell cultures. Challenge of IL-22 knockout mice resulted in a phenotype that mimicked the dectin-1-/- mice. Moreover, neutralization of IL-22 improved lung function. Together, the data suggest that dectin-1 and IL-22 contribute to pathology during a model of fungal asthma. As neutrophils have been shown to be critical in host defense during invasive aspergillosis, we sought to determine the importance of other cell types during infection. We show that during an Aspergillus fumigatus infection, eosinophils are recruited to the lungs. Using eosinophils-deficient dblGATA-1 knockout mice, we demonstrate a requirement for eosinophils in optimal clearance. Elevated fungal burden observed in dblGATA-1-deficient mice was accompanied with reduced levels of Epx and Prg2. As a defect in other cellular recruitment was not observed in eosinophil-deficient mice, we investigated the killing ability of eosinophils generated from bone marrow. We show that eosinophils are able to respond to Aspergillus fumigatus through pro-inflammatory and Th2 cytokine production and control fungal growth in vitro. Collectively, our data shows a crucial role of eosinophils in host defense during a mouse model of IA.

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