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The Dynamic Role of Ethanolamine Utilization During Salmonella Infection

Anderson, Christopher
Thesis/Dissertation; Online
Anderson, Christopher
Kendall, Melissa
Bacterial pathogens must sense and respond to the surrounding environment to modulate gene expression and successfully adapt to a newly infected host. Pathogen adaptation strategies are fundamentally signal transduction pathways. Each newly encountered environment, for example within a host, will contain a defined set of chemical and physical signals. Pathogens routinely recognize these signals via some sort of membrane-bound receptor or through a transport system that shuttles the signal into the cytosol of the bacterium. The signal is then propagated by transcription factors that will either induce or repress certain genes in response to a given signal. These signaling pathways ultimately result in the production of effector proteins, whether they are secreted virulence factors or metabolic enzymes, which are specifically required in this particular environment and promote bacterial replication and survival. The bulk of research within the field of microbiology has focused on the effector proteins that promote bacterial replication and survival, but less is known about the upstream transcription factors or the actual signals themselves that promote the expression of effectors. These studies have revealed a great deal about the fundamental strategies used by pathogens to survive within the host environment; however, effector proteins are commonly pathogen specific and novel therapeutics or vaccines designed against these effectors have produced moderate results. Instead, it is possible that a wide range of pathogens recognize the same signals within the host. Identifying the signals that activate expression of crucial virulence factors may lead to the development of novel broad-spectrum therapeutic interventions. We determined that the foodborne pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) senses and responds to the molecule ethanolamine (EA) within three distinct host environments during infection. During intestinal colonization, S. Typhimurium utilizes EA as a metabolite and as a signaling molecule to promote robust colonization. Next, during early stages of systemic infection, EA signals to promote virulence gene expression and intramacrophage survival. Of note, the EA transporter EutH is required for vacuole adaptation within macrophages for both S. Typhimurium and Listeria monocytogenes, indicating that EA is a conserved signal for host adaptation. Finally, S. Typhimurium EA utilization impacts host biology and immune response during later stages of infection. Overall, this work demonstrated how one signaling molecule (EA) is sensed within various host environments to promote different functional outcomes in vivo. Furthermore, we identified a link between bacterial EA utilization and host cell biology and overall immune response. The ability to utilize EA is conserved across many Gram-negative and Gram-positive pathogens. Therefore, our findings may highlight a general strategy for host adaptation that allows bacterial pathogens to promote their own replication and survival while simultaneously evading the host immune response.
University of Virginia, Department of Microbiology, PHD (Doctor of Philosophy), 2017
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PHD (Doctor of Philosophy)
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