Date of Award

2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biochemistry and Molecular Biology

College

College of Graduate Studies

First Advisor

Yong-Mei Zhang

Second Advisor

Christopher Davies

Third Advisor

Harold May

Fourth Advisor

Claudia Rocha

Fifth Advisor

David Long

Sixth Advisor

Patrick Flume

Abstract

Bacterial group behaviors are advantageous during an infection to thwart immune cell attack and resist deleterious changes in the environment. Bacteria use a chemical messaging system in order to coordinate the phenotypes in the environment. In Pseudomonas aeruginosa, the Pseudomonas quinolone signal (Pqs) quorum-sensing system produces alkylquinolones that regulate virulence factor production and also perform extracellular roles. Two alkylquinolones, 2-heptyl-4-quinolone (HHQ) and 2- heptyl-3-hydroxy-4-quinolone (PQS) activate transcriptional regulator PqsR for subsequent production of quinolones and phenazines, iron chelation, and autolysis. The most abundant quinolone produced from the Pqs system is 2,4-Dihydroxyquinoline (DHQ); however, DHQ has no known function. We demonstrated mutants only able to produce DHQ maintained virulence towards a model of bacterial infection and in vitro virulence factor production. Furthermore, we identified a potential extracellular role for DHQ against both epithelial cells and macrophages that resulted in reduced replication, viability, and cytokine production. As a signaling molecule, DHQ activated PqsR to bind to the promoter region of pqsA for transcription. Finally, we determined the impact of DHQ on cystic fibrosis patient health and its correlation to lung function. Taken together, our findings suggest DHQ is capable of activating PqsR as a redundant QS molecule, but may play a significant role against host cells during infection.

Rights

All rights reserved. Copyright is held by the author.

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