Host adaptation, T cell immunity, and transmission ecology of Francisella tularensis
Open Access
- Author:
- Williamson, David Ross
- Graduate Program:
- Immunology and Infectious Diseases
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- February 27, 2018
- Committee Members:
- Girish Soorappa Kirimanjeswara, Dissertation Advisor/Co-Advisor
Girish Soorappa Kirimanjeswara, Committee Chair/Co-Chair
Na Xiong, Committee Member
Mary J Kennett, Committee Member
Reka Z Albert, Outside Member
Margherita Teresa-Anna Cantorna, Committee Member - Keywords:
- Francisella
tularemia
pH
mechanosensitive channel
T Cell
CD8 - Abstract:
- Pathogenic microorganisms are already responsible for a significant burden of disease, and this burden is predicted to grow as the prevalence of antimicrobial resistance rises. A comprehensive strategy to combat infectious disease must address the problem at multiple levels, including: 1) pathogen adaptation to the host niche, 2) vaccination strategies to achieve protective adaptive immunity, and 3) transmission and ecological persistence of the pathogen. This dissertation involves studies at each of these three levels for the Tier 1 select agent Francisella tularensis. In the first study, a hypothetical protein required by F. tularensis for successful adaptation to the pH of the host niche is identified and characterized. Bacteria lacking this protein exhibit a pH-dependent growth defect in media and host cells, are highly attenuated in mouse models of tularemia, display aberrant morphology with inner-outer membrane separation at pH 7.4, and display an altered metabolic profile at pH 7.4. This study demonstrates that bacterial pH-adaptation strategies are relevant even at the near-neutral physiological pH of mammals. The second study focuses on antigen-specific CD8+ T cell responses to vaccination strategies with the F. tularensis Live Vaccine Strain. Vaccination via the intranasal route, which can protect from respiratory challenge with highly virulent strains, elicits more antigen-specific CD8+ T cells in the lung-draining mediastinal lymph node compared to non-protective scarification vaccination. An intranasal booster of scarification-primed mice overcomes this deficiency while avoiding the morbidity associated with primary intranasal vaccination, suggesting a novel safe and effective vaccination strategy for the prevention of respiratory infections. The final study involves identification of a mechanosensitive channel that is required for contamination of fresh water by F. tularensis. This is the first study to directly demonstrate the relevance of these channels in contamination of fresh water by infected host animals. The channel protects from osmotic downshock despite lacking much of the C-terminal vestibule domain found in prototypical mechanosensitive channels, and likely contributes to the thousands of cases of oropharyngeal tularemia that have result from water contamination by F. tularensis subsp. holarctica.