All ETDs from UAB

Advisory Committee Chair

Claude H Steele

Advisory Committee Members

Laurie E Harrington

Hubert Tse

Daniel Bullard

Suzanne Michalek

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine


The opportunistic fungal pathogen Aspergillus fumigatus is a ubiquitous mold that causes severe, invasive life-threatening infections in patients that are severely immunocompromised. Major risk factors include neutropenia, neutrophil dysfunction and immunosuppressive therapies. Recently, however, rising incidences of colonizing A. fumigatus have been reported in patients without classical risk factors. We sought out to elucidate non-classical pre-disposing conditions that may render a lung environment susceptible to fungal colonization as well as mechanisms involved in immune defense against the invading fungal pathogen. Further defining a role for Dectin-1 in an Aspergillus fumigatus infection, we demonstrated a critical role for Dectin-1 dependent interleukin-22 (IL-22) in the clearance of A. fumigatus. Mice deficient in IL-22 demonstrated higher lung fungal burden after A. fumigatus challenge in the presence of impaired IL-1α, TNFα, CCL3/MIP-1a and CCL4/MIP-1b production, lower neutrophil recruitment, yet intact IL-17A production. Moreover, lung lavage fluid from A. fumigatus-challenged IL-22 deficient mice had compromised anti-fungal activity against A. fumigatus in vitro. Furthermore, we show that despite enhanced recruitment of inflammatory cells to the lungs of chlorine-exposed A. fumigatus challenged mice, these cells demonstrated a profound impairment in generating superoxide. Following exposure to Cl2, mice challenged with A. fumigatus demonstrated a significantly higher fungal burden in the presence of higher IL-6 and TNFα, but lower IL-17A and IL-22 in the lungs compared to mice that were not challenged with A. fumigatus. Collectively, our results indicate that early innate lung defense against A. fumigatus is mediated by Dectin-1 dependent IL-22 production. Furthermore, a predisposing condition such as chlorine exposure prior to fungal colonization markedly impairs the antimicrobial activity and inflammatory reactivity of myeloid cells in the lung leading to increased susceptibility to opportunistic pathogens.



To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.