Dissertation
The Role of Adenosine Monophosphate Protein Kinase (AMPK) Activation In Francisella tularensis Intracellular Replication
Washington State University
Doctor of Philosophy (PhD), Washington State University
2022
DOI:
https://doi.org/10.7273/000005067
Abstract
Pathogens are infectious microorganisms that cause disease. Following transmission to a susceptible host, some pathogens replicate in extracellular spaces while others invade and replicate inside host cells either in modified cellular vesicles or freely in the host cell cytoplasm. Once inside the cell, intracellular pathogens must harvest metabolizable nutrients to successfully proliferate and cause disease. However, the host innate immune response typically restricts access to these crucial nutrients. Therefore, intracellular pathogens must express mechanisms to acquire sequestered nutrients within the cell. Francisella tularensis is a Gram-negative facultative intracellular pathogen that causes a zoonotic disease known as tularemia. The bacterium is highly virulent with a low infectious dose and a broad host range. Upon infection, F. tularensis encounters a wide range of environments inside the host cell. Following internalization, F. tularensis initially resides in a phagosome, termed the Francisella containing vacuole (FCV), which the bacterium rapidly degrades to facilitate access to the cytoplasm. Once inside the cytoplasm, F. tularensis undergoes extensive rounds of replication with peak replication at approximately 24 hours. This rapid replication is one of the hallmarks of F. tularensis pathogenesis. In this dissertation, we aimed to understand how the regulation of host cell metabolism contributes to F. tularensis intracellular replication and how the bacterium may exploit host metabolic pathways to harvest metabolizable nutrients from the cell. In this thesis, we show that activation of adenosine monophosphate kinase (AMPK) contributes to F. tularensis intracellular growth. We show activated AMPK regulates lipid metabolism during infection resulting in the liberation of triglycerides that F. tularensis can import and use as a carbon source to undergo bacterial replication. We also found that exogenous AICAR can led to AMPK activation which rescues the intracellular growth of a F. tularensis purine auxotroph. Altogether, these studies identified how F. tularensis manipulates and exploits host metabolism to harvest nutrients essential for bacterial replication and survival. Furthermore, these studies impact the understanding of host metabolic-bacterial interactions that may contribute to bacterial pathogenesis in general.
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Details
- Title
- The Role of Adenosine Monophosphate Protein Kinase (AMPK) Activation In Francisella tularensis Intracellular Replication
- Creators
- Sedelia Dominguez
- Contributors
- Thomas Kawula (Advisor)Alan Goodman (Committee Member)Leigh Knodler (Committee Member)Michael Konkel (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- School of Molecular Biosciences
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 146
- Identifiers
- 99901019941401842
- Language
- English
- Resource Type
- Dissertation