Date of Award

Summer 2022

Document Type

Thesis (Ph.D.)

Department or Program

Microbiology and Immunology

First Advisor

Robert A. Cramer Jr.

Second Advisor

George A. O'Toole Jr.

Third Advisor

Carey D. Nadell

Abstract

Aspergillus fumigatus is a saprophytic filamentous fungus that participates in environmental carbon and nitrogen cycles through the degradation of complex organic substrates. In addition to its ecological role, A. fumigatus is the primary causative agent of a spectrum of diseases depending on the immune status of the individual, the most lethal of which is invasive aspergillosis (IA). Treatment strategies for IA are limited and far too frequently fail. Despite the high rates of treatment failure, antifungal resistance remains relatively low, albeit rising at a concerning rate. Insights into this discrepancy between the rate of treatment failure and the rate of antifungal drug resistance are critical to improving the morbidity and mortality associated with IA. During infection, A. fumigatus grows in a communal form termed a biofilm. Biofilms of A. fumigatus have been demonstrated to have greater resistance to antifungal treatment and thus this communal mode of growth may drive the discrepancy mentioned above.

In this dissertation, we provide insight into the interplay between metabolism, biofilm physiology, and antifungal drug resistance of A. fumigatus. We identify an alanine aminotransferase encoding gene, alaA, that is critical for the regulation of cell wall and extracellular matrix polysaccharides of A. fumigatus biofilms. We determined that alaA is essential for echinocandin resistance of A. fumigatus biofilms in vitro and in vivo. Utilizing chemical analogs of L-alanine we reveal that L-alanine acts as a signaling molecule in A. fumigatus, and further go on to determine that L-alanine signaling regulates metabolism via a mechanism that is independent of the major known regulators of carbon metabolism. The results presented in this dissertation contribute to our understanding of A. fumigatus metabolism, biofilm physiology, and antifungal drug resistance.

Available for download on Thursday, July 20, 2023

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