Type
Text
Type
Dissertation
Date
2011-09-13
Keywords
TolC | Francisella tularensis
Language
en_US
Source
This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree.
Identifier
http://hdl.handle.net/11401/71069
Publisher
The Graduate School, Stony Brook University: Stony Brook, NY.
Format
application/pdf
Abstract
Francisella tularensis is the causative agent of tularemia. There are five subspecies of F. tularensis, three that are pathogenic to humans. F. tularensis subsp. tularensis is extremely pathogenic and sometimes fatal. F. tularensis subsp. holarctica causes a less severe disease. The live vaccine strain (LVS) is derived from a holarctica strain and retains virulence in the mouse. F. tularensis subsp. novicida causes disease in immunocompromised persons. F. tularensis is classified as a Category A agent of iv bioterrorism by the Centers for Disease Control due to its low infectious dose, ease of aerosol dissemination and capacity to cause high morbidity and mortality. F. tularensis is a Gram-negative, intracellular pathogen. Gram-negative bacteria have two cellular membranes, making it necessary for the development of highly sophisticated secretion systems. One such pathway is the type I section system (TISS), which functions in both drug efflux and protein secretion. The TISS consists of three proteins: an inner membrane protein, often containing an ATP binding cassette (ABC), a periplasmic protein, and an outer membrane protein (OMP). The TolC protein of Escherichia coli represents the canonical T1SS OMP. Genomic evidence supporting the existence of a TISS in F. tularensis includes two orthologs of the E. coli tolC gene, termed tolC and ftlC, and 15 putative ABC proteins. In this dissertation, I constructed tolC and ftlC deletion mutations in the LVS and investigated the role these genes play in survival and virulence. Antibiotic sensitivity assays revealed that both TolC and FtlC function in drug efflux. However, only TolC was determined to be an essential virulence determinant, as the tolC mutant was avirulent in the mouse model and defective in colonizing organs. In vitro analysis revealed that F. tularensis actively inhibits host cell death and secretion of proinflammatory cytokines in a TolC-dependent manner. Based on these results, we propose that in the absence of TolC F. tularensis induces rapid host cell death and a large proinflammatory response. This causes the bacteria to lose its intracellular replicative niche, and with insufficient bacterial numbers the pathogen is cleared by the increased innate immune response of the host.
Recommended Citation
Platz, Gabrielle, "Role of TolC homologs in the Virulence of
Francisella tularensis" (2011). Stony Brook Theses and Dissertations Collection, 2006-2020 (closed to submissions). 276.
https://commons.library.stonybrook.edu/stony-brook-theses-and-dissertations-collection/276