Date of Award

12-2010

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Biomedical Sciences

Track

Microbial Pathogenesis, Immunology, and Inflammation

Research Advisor

Mark A. Miller, Ph.D.

Committee

James E. Bina, Ph.D. Richard E. Lee, Ph.D. Tony N. Marion, Ph.D. Michael A. Whitt, Ph.D.

Keywords

bacteria, pathogen, bioweapon, Francisella, plasminogen, tularemia

Abstract

Francisella tularensis (FT) is a Gram-negative coccobacillus and causative agent of a life-threatening disease commonly referred to as tularemia. Due to the highly infectious nature of the organism, its previous development as a biowarfare agent and its potential use in acts of bioterrorism, this bacterium is listed as a Category A select agent by the Centers for Disease Control and Prevention (CDC). Efforts to understand the pathogenic mechanisms of FT within the host environment are vital for the development of safe and effective vaccines, as well as treatments, against tularemia. Though considered an intracellular pathogen, FT research of late has shown an abundance of extracellular bacteria in the plasma fraction of host's blood during infection. The goal of these studies was to identify and characterize the interactions of Francisella tularensis with components of the host fibrinolytic system.

Because many bacterial pathogens utilize proteins found in the host plasma fraction as a means to augment dissemination as well as to defend themselves against components of the host immune system, I first sought to determine if FT was able to bind these on its surface in vitro using fresh frozen human plasma. By using an ELISA assay I was able to detect significant levels of plasminogen and fibronectin binding to the bacterial cell surface. Based on this observation, further studies were designed to dissect possible in vitroand in vivo functions of these FT-bound host proteins.

Plasminogen (PLG) is a zymogen that upon activation is converted into the serine protease plasmin, which plays a key role in the proteolytic degradation of fibrin blood clots. Many pathogenic organisms have taken advantage of both the broad-specificity and abundance of this circulating host protein by binding it to their surface, which not only gives the pathogen an ability to degrade extracellular matrix components for dissemination but also aids in the defense against host immune responses. The ability of FT to acquire surface bound PLG that can be activated may be an important virulence mechanism that results in an increase in initial infectivity, survival, and/or dissemination of this bacterium in vivo.

DOI

10.21007/etd.cghs.2010.0053

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