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Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation




Microbiology, Immunology, and Molecular Genetics

First Advisor

Dr. Brian Stevenson


Gene regulatory networks are composed of interconnected regulatory nodes created by regulatory factors of multiple types. All organisms finely tune gene expression in order to adapt to and survive within their current niche. Obligate parasitic bacteria are under extreme pressure to quickly and appropriately adapt their gene regulatory programs in order to survive within their given host. Borrelia burgdorferi is one such organism and persists in nature by alternating between two hosts; Ixodes spp. ticks and small vertebrate animals. These two hosts represent drastically different environments; requiring a unique gene regulatory program to survive and transmit between them. Microbiologists have long sought to better understand exactly what stimuli pathogens sense and how that information is relayed in to physiologic adaptation.

In this work I aimed to examine two parts of this interesting field. First, I sought to better understand the stimuli B. burgdorferi sense in order to adapt to their hosts by testing several hypotheses centered on the general notion that B. burgdorferi senses both internal and external metabolic cues as primary signals for adaptation. I demonstrated that a second messenger system immediately downstream of a critical metabolic pathway is important during vertebrate infection and that a key regulator of virulence is itself regulated by a factor involved in DNA replication.

Second, I sought to better define the topology of gene regulatory networks, known and unknown, that are important for the ability of the bacteria to adapt. The work in this section focus on the idea that B. burgdorferi gene regulatory networks are extremely complex and are not currently well defined in the literature. My studies revealed that B. burgdorferi possesses a large number of previously undefined regulatory targets, including extended 5’ and 3’ UTRs of known genes, and encodes several hundred-putative small non-coding RNAs. Furthermore, I demonstrate that two essential regulatory factors share substantial, independent, overlap in their regulons highlighting the still undefined complexity of regulatory networks at play in B. burgdorferi.

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