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Role of Innate Host Defenses in Acute and Vaccination Models of Pneumonic Tularemia

Schmitt, Deanna (2012) Role of Innate Host Defenses in Acute and Vaccination Models of Pneumonic Tularemia. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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The innate immune system is the first line of defense against invading pathogens. In order to establish a productive infection, microorganisms must effectively evade host defenses. The intracellular bacterium Francisella tularensis possesses multiple strategies to actively and passively avoid recognition and clearance by the host. Moreover, F. tularensis elicits a delayed innate immune response compared to other respiratory pathogens such as Klebsiella pneumoniae. Whether this immune response plays a beneficial or detrimental role in tularemia pathogenesis is not known. In this thesis, the contribution of innate host defenses against F. tularensis was evaluated in two different settings: acute infection of naïve animals with a type A strain and after vaccination with the live vaccine strain (LVS). First, a comprehensive comparison of the early host response to the virulent type A F. tularensis strain Schu S4 and the attenuated type B strain LVS revealed several unique features of type A F. tularensis infection. The most significant immunological difference between these strains was a reduction in the number of viable lung cells, particularly NK cells and T cells, in Schu S4-infected mice. Since the decline in NK cells correlated with morbidity and mortality, the role of these cells in host defense against Schu S4 infection was evaluated. Modulation of NK cells did not have a demonstrable effect on Schu S4 infection in vivo suggesting these cells do not contribute to immunity against type A F. tularensis. In the final part of this thesis, LVS was genetically modified in order to better stimulate antigen-presenting cells and improve vaccine efficacy. Although LVS FTL_0883 mutants elicited increased proinflammatory cytokine production and costimulatory molecule expression by macrophages and DCs, they failed to provide better protection against Schu S4 challenge than wild-type LVS. The data presented in this thesis expands our current knowledge of the innate immune response to F. tularensis and provides insight into tularemia vaccine development and immunotherapy.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorNau, Gerardgjnau@pitt.eduGJNAU
Committee MemberDarville, L.
Committee MemberFlynn, JoAnne L.joanne@pitt.eduJOANNE
Committee MemberOury, Tim Dtdoury@pitt.eduTDOURY
Committee MemberSalter, Russellrds@pitt.eduRDS
Date: 25 August 2012
Date Type: Publication
Defense Date: 8 August 2012
Approval Date: 25 August 2012
Submission Date: 23 August 2012
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 176
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Francisella tularensis, Host Defense, Innate Immunity, Vaccination, Natural Killer Cells, Antigen Presenting Cells
Date Deposited: 25 Aug 2012 15:41
Last Modified: 25 Aug 2017 05:15


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