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

[摘要] 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.

[发布机构] the University of Pittsburgh