All ETDs from UAB

Advisory Committee Chair

Chad Steele

Advisory Committee Members

Lesley Smythies

David Briles

David Chaplin

Frances Lund

Document Type

Dissertation

Date of Award

2017

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

A. fumigatus is one of the most common fungal isolates with clinical disorders ranging from mild to severe. The development of Aspergillus-induced allergic and invasive fungal infections is a major health concern in several patient populations. IL-1 family members have been shown to play critical roles in host defense against A. fumigatus. IL-33, an IL-1 family member widely study in allergic and inflammatory diseases, was induced upon acute exposure to A. fumigatus. IL-33 receptor knockout mice, (Il1rl1-/-), demonstrated lower lung fungal burden in the presence of enhanced IL-1α, IL-1β, IL-6, IL-17A, IL-22, and PGE2 production. Administration of IL-33 to normal mice significantly reduced the production of IL-17A, IL-22, and PGE2. In vivo inhibition of cyclooxygenase in Il1rl1-/- mice reduced not only IL-17A and IL-22 but also IL-1α, IL-1β, and IL-6 which corresponded with a defect in lung fungal clearance. Furthermore, culturing immune cells in the presence of a PGE2 receptor agonist augmented production of IL-17A and IL-22, whereas, culturing in the presence of a PGE2 synthase inhibitor attenuated IL-17A and IL-22 production. Together, these data suggest that IL-33 is a negative regulator of innate IL-17A and IL-22 production via PGE2. The cell wall of A. fumigatus is comprised of several polysaccharides including chitin. Exposure to chitin has been linked to fungal recognition and sensitization. In re-sponse to chitin, epithelial cells secrete chitinases such as acidic mammalian chitinase (AMCase, Chia) to break down chitin; however, the specific role of AMCase in allergic and invasive aspergillosis is not well defined. During an invasive aspergillosis model, Chia-/- mice demonstrated increased fungal clearance in the lungs. Similarly to Il1rl1-/-, a deficiency in AMCase corresponded in increased levels of IL-1β, IL-17A, IL-22, and PGE2. In an allergic asthma model associated with chronic A. fumigatus exposure, Chia-/- mice displayed less asthma severity with reduced airway hyperresponsiveness along with decreased levels of pro-allergic chemokines (CCL17/CCL22). Additionally, Chia-/- mice exhibited significant decreases in IL-17A and IL-22, but not type 2 responses (IL-4/IL-5/IL-13). Collectively, these data suggest that AMCase promotes pathology during acute and chronic exposure to Aspergillus by the regulation of the IL-17A/IL-22 axis.

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