Abstract
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 Francisella tularensis, the agent of tularemia, 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. The pathogenesis of F. tularensis is not fully understood, and research has failed to develop an effective vaccine to this date. In the current study, we 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-ɣ-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, we demonstrate that targeting inactivated F. tularensis (iFt) to Fcγ receptors (FcɣRs) via intranasal immunization with mAb-iFt complexes, a proven vaccine strategy in our laboratories, reverses the anti-inflammatory effects of the bacterium on macrophages by down-regulating production of IL-10. More specifically, we observed that 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 Fc receptors.
Highlights
For many intracellular bacteria the induction of a robust innate immune response is a critical factor in host protection and bacterial clearance [1,2,3]
We have previously demonstrated that targeting inactivated F. tularensis bacteria to the Fcγ receptors (FcγRs) in mice, via immunization with mAb-iFt immune complexes, resulted in: (1) enhanced uptake and presentation of the immunogen by professional antigen presenting cells, (2) increased recruitment and activation of dendritic cells in the lungs of immunized mice, (3) enhanced F. tularensis-specific cytokine and antibody responses, (4) generation of effector memory CD4+ T cells, and (5) increased protection against F. tularensis infection [19, 25, 26]
Peritoneal exudate cell (PEC) were further stimulated with LVS ex vivo for 24 hours and the cytokine levels in the supernatant were measured by the BD Biosciences Cytometric Bead Array (CBA)
Summary
For many intracellular bacteria the induction of a robust innate immune response is a critical factor in host protection and bacterial clearance [1,2,3]. The induction of innate immunity is triggered upon recognition of bacterial components such as lipopolysaccharides, peptidoglycans, or bacterial DNA by cellular receptors and regulated by a number of cytokines including IL-12, TNF-α and IFN-γ [4, 5]. F. tularensis can be transmitted through insect bites, infected carcasses, contaminated water, and inhalation of contaminated air, inhalation of as little as 1–2 bacteria can lead to respiratory failure and death if left untreated [13]. For this reason, the Centers for Disease Control and Prevention has designated F. tularensis as a Category A biological agent [14]. Since no licensed vaccine for tularemia is currently available in the United States, there is a need for development of an effective vaccine
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