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> *Dissertation Defense Announcement:
> To:  The George Mason University Community*
>
> *Anne B. Verhoeven
> PhD Biosciences Candidate
> *
> *Date:   Thursday June 17, 2010
> Time:   10:30 a.m. 
> Place:  George Mason University
> ** 	     Room 256, Bull Run Hall
> 	     Prince William campus <http://www.gmu.edu/resources/visitors/findex.html>
>   
> Dissertation Chair: Dr. Monique van Hoek
> Committee members: Dr. Emanuel Petricoin III, Dr. Yuntao Wu, Dr. Timothy Born*
>
> *Title: "An Analysis of Signaling Pathways Activated by /Francisella Tularensis/ Infection"*
>
> A copy of the dissertation is on reserve in the Johnson Center 
> Library, Fairfax campus.  The doctoral project will not be read at the 
> meeting, but should be read in advance.
>
> All members of the George Mason University community are invited to 
> attend.*
> *
>
> *ABSTRACT:
> *
> /Francisella tularensis /is a zoonotic, gram negative pathogen that in 
> recent years has become a pathogen of increasing interest because of 
> its bioterrorism implications.  /Francisella /has been classified as a 
> Type A pathogen by the CDC.  It is capable of producing severe 
> infection with doses as low as 10 organisms.  The possible threat of 
> /Francisella /as a biological weapon makes understanding its specific 
> pathogenicity of utmost importance. 
> /Francisella /is an intracellular pathogen that enters the cell 
> through an unknown method.  Infection from /Francisella /occurs in 
> many different cell types, including macrophages, hepatocytes, and 
> endothelial cells.  Once in the cell, /Francisella /is encapsulated in 
> a phagosome.  Between 2-4 hours after the initial infection 
> /Francisella /escapes the phagosome and proceeds to replicate in the 
> hosts cytosol.  Previous studies have demonstrated that /Francisella 
> /inhibits the release of pro-inflammatory cytokines such as TNF-alpha, 
> IL-1, IL-12, and IL-8, thus hampering the ability of the innate immune 
> system to respond to infection.  Also, there is an increase of IL-10 
> seen during /Francisella /infection.  IL-10 is an anti-inflammatory 
> cytokine that further decreases the innate immune system response.  
> The lack of proper cytokine production might be caused by 
> /Francisella/'s ability to block the TLR pathways, CR3 pathways, and 
> the apoptosis pathways, further impeding the innate immune response.  
> Interestingly, /Francisella /does not employ any known secretion 
> systems, such as type III or type IV secretion systems that are 
> commonly found in pathogenic bacteria.  Nor does it produce toxins 
> that could explain its ability to block cell signaling pathways.  The 
> mechanism used by /Francisella /directly interacts with host cell 
> pathways is still unknown.
> *We hypothesize that by looking at specific pathways that are 
> activated during infection of J774A.1 macrophages by /Francisella 
> tularensis /LVS and /Francisella novicida /that we will be able to 
> obtain a phosphorylation map of activated host cell responses*.  *We 
> hope that this map will point out virulence and pathogenic factors 
> that /Francisella/ employs when it is infecting host's cells which 
> could lead to better therapeutics as well as possible vaccine 
> targets*.  The steps that we will use to accomplish this task are: 1) 
> the use of Reverse Phase Protein Microarray analysis to generate a 
> phosphorylation map of /Francisella /LVS and /Francisella novicida/ 
> infection in J774A.1 cells, 2) validation of this map through western 
> blots and analysis of previous reported data on specific signaling 
> pathways, 3) comparison of different phosphorylation maps of 
> /Francisella novicida /and /Francisella /LVS to determine differences 
> between the strains, and 4) in a separate study, we will examing 
> changes in gene expression in human lung epithelial cells through the 
> use of microarrays to determine the difference in host cell gene 
> transcription between uninfected A549 cells and /Francisella /LVS 
> infected A549 cells.
>
>
> ###
>