The Role of Nutritional Virulence in Francisella tularensis Pathogenesis Public Deposited

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  • March 19, 2019
Creator
  • Steele, Shaun
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Intracellular pathogens and infected host cells compete with each other for survival and limited resources, such as nutrients. To limit infections, host cells have evolved a multitude of overlapping innate defense mechanisms; but, intracellular pathogens evade or exploit these defenses to replicate within cells. The bacterial pathogen Francisella tularensis manipulates several host defense mechanisms to proliferate within cells. F. tularensis replicates to extremely high densities within host cells and transfers to uninfected cells without inducing significant host cell death. The efficiency of F. tularensis intracellular replication and spread raises two fundamental questions that form the core of my dissertation work: how does F. tularensis acquire enough nutrients from the host cell to sustain rapid proliferation and how does F. tularensis infect new cells while maintaining the viability of infected host cells? Here I show that F. tularensis exploits novel host defense mechanisms to acquire intracellular nutrients and to transfer between cells. F. tularensis harvests autophagy-derived amino acids from the host to sustain rapid intracellular proliferation. These amino acids are used by F. tularensis to build proteins and as a carbon source to build other molecules, such as nucleic acids. Additionally, I found that F. tularensis transfers to macrophages when the macrophage ingests a portion of cytosol from a live, infected neighboring cell, a process that we have termed metadosis. My dissertation work contributed to our understanding of how pathogens interact with host cells. My work on autophagy helped to lay the groundwork for a paradigm of ‘nutritional virulence’ and my work has translated well in other intracellular pathogens. I anticipate that my work on metadosis will lay the foundation for future studies on how bacteria spread within the host and how antigen presenting cells acquire antigen to interact with the adaptive immune system.
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  • In Copyright
Advisor
  • Kawula, Thomas
  • Moorman, Nathaniel
  • Goldman, William
  • Miao, Edward
  • Braunstein, Miriam
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2015
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  • Chapel Hill, NC
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