All ETDs from UAB

Advisory Committee Chair

Chad Steele

Advisory Committee Members

Alex Szalai

Laurie Harrington

Kevin Harrod

Sasanka Ramanadham

Chad Steele

Document Type

Dissertation

Date of Award

2020

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Aspergillus fumigatus is an environmental airborne fungus that acts as both an opportunistic pathogen and an allergen. In immunocompromised hosts, A. fumigatus can germinate in the lung, cause tissue damage and pneumonia, and disseminate to other organs, causing a disease termed invasive aspergillosis (IA). In severe asthma, sensitization to fungi such as A. fumigatus is associated with more severe disease. Determination of host and fungal factors that drive immunoprotection versus immunopathogenesis in both of these settings will ultimately enable therapeutic modulation of immune responses to improve disease outcomes. In this body of work, we build on recent findings that implicate eicosanoids and chitinases/chitinase-like proteins in immune responsiveness to A. fumigatus. We define the major roles of two host factors: 12/15-lipoxygenase (12/15-LOX) during IA and chitinase 3-like 1 (Chi3l1) during A. fumigatus associated allergic asthma. We report that 12/15-LOX supports fungal clearance and prevents lethal lung damage during IA by promotion of inflammatory cytokine production in the lung and neutrophil granulopoiesis in the bone marrow. In the context of fungal asthma we report that Chi3l1 drives Th2 inflammation including production of IL-4 and IL-5 and recruitment of eosinophils but paradoxically protects from development of airway hyperresponsiveness.

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