All ETDs from UAB

Advisory Committee Chair

Chad H Steele

Advisory Committee Members

Lisa Schweibert

Casey T Weaver

Lesley Smythies

John F Kearney

Document Type

Dissertation

Date of Award

2017

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Fungal pathogens contribute to a wide range of diseases that are largely dependent on the host’s immune state. In the case of immune suppression, Aspergillus fumigatus is the causative agent of invasive aspergillosis. Furthermore, asthmatics sensitized to fungi such as Aspergillus fumigatus are reported to have more severe asthma. We have previously described a role for IL-22 in mouse models of invasive aspergillosis and fungal asthma. IL-22 was found to play a protective role in invasive aspergillosis, while it was found to play an immunopathogenic role in asthma. Here we describe the cell sources of IL-22 in both models. We found that  T cells, invariant natural killer T cells, and ILC3s are the major producers of IL-22 in both disease models. We go on to describe the roles of IL-7, IL-15, and IL-21 in the pathogenesis of invasive aspergillosis, and IL-22 generation. IL-22 production in invasive aspergillosis is dependent on IL-7, and IL-7 is necessary for the maintenance of iNKTs and ILC3s. Absence of the IL-15R lead to enhanced IL-22 production, but no effect on the size of any of the IL-22 producing cell types. However, iNKTs and  T cells express more IL-22 per cell in IL-15R deficient mice compared to WTs. IL-22 was only partially dependent on IL-21 and, similar to IL-7, was important in the maintenance of iNKTs and  T cells. We have also found IL-22 to be completely dependent on RORγt and MyD88, partially dependent on Ahr, and independent of Trif. In an assessment of human asthmatics, we observed significantly higher levels of IL-7 in lavage fluid from subjects that were sensitized to fungi compared to subjects that were atopic but not fungal sensitized. Mice administered exogenous IL-7 showed significant increases in airway hyper-responsiveness, elevated type 2 cytokines (IL-4, IL-5, IL-13), pro-allergic chemokines (CCL17, CCCL22), pro-inflammatory cyto-kines (IL-1, IL-1), and IL-22. Finally, targeting IL-7 signaling via CD127 blockade in vivo resulted in attenuated IL-22 production and lower CCL22 levels. Collectively these results describe previously unreported roles for common gamma-chain cytokines in Aspergillus associated diseases.

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