Date of Award

Fall 9-11-2015

Degree Type

Dissertation

Degree Name

PhD Molecular Bioscience

Department

Biology

Advisor

Constantine Bitsaktsis, Ph.D

Committee Member

Allan D. Blake, Ph.D

Committee Member

Daniel B. Nichols, Ph.D

Committee Member

Heping Zhou, Ph.D

Committee Member

Rico Gunawan, Ph.D

Keywords

Francisella tularensis, Live vaccine strain, Antigen presenting cells, Immune complex, Fc receptor, Lipopolysaccharide

Abstract

Francisella tularensis is a gram-negative intracellular bacterium and the etiologic factor of a potentially fatal disease tularemia. Due to its high infectivity the Centers for Disease Control and Prevention has designated F. tularensis as a Category A biological agent. Nevertheless, the pathogenesis of F. tularensis is not fully understood and research has failed to develop an effective vaccine. Production of pro-inflammatory cytokines by innate immune cells at the early stages of bacterial infection is important for host protection against the pathogen. Many intracellular bacteria, including F. tularensis, utilize the anti-inflammatory cytokine IL-10, to evade the host immune response. It is well established that IL-10 has the ability to inhibit robust antigen presentation by dendritic cells and macrophages, thus suppressing the generation of protective immunity. In the current study, it is hypothesized that F. tularensis polarizes antigen presenting cells during the early stages of infection towards an anti-inflammatory status characterized by increased synthesis of IL-10, and decreased production of IL-12p70 and TNF-α in an IFN-γ-dependent fashion. In addition, F. tularensis drives an alternative activation of alveolar macrophages within the first 48 hours post-infection, thus allowing the bacterium to avoid protective immunity. Furthermore, for the first time, this study demonstrates that targeting inactivated F. tularensis (iFt) to Fcγ receptors (FcγRs) via intranasal immunization with mAb-iFt complexes reverses the anti-inflammatory effects of the bacterium on macrophages by ix down-regulating production of IL-10 and mediates generation of F. tularensis-specific, IFN-γ secreting effector memory CD4+ T cells. Furthermore, targeting of iFt to FcγRs enhances the classical activation of macrophages not only within the respiratory mucosa, but also, systemically, at the early stages of infection. These results provide important insight for further understanding the protective immune mechanisms generated when targeting immunogens to Fcγ receptors validating its potential as a universal vaccine platform against mucosal pathogens.

Included in

Biology Commons

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