Targeting of a fixed bacterial immunogen to Fc receptors reverses the anti-inflammatory properties of the gram negative bacterium, Francisella tularensis, during the early stages of infection (VAC8P.1055)

Abstract

Abstract Production of pro-inflammatory cytokines by innate immune cells at the early stages of bacterial infection is important for host protection. Many intracellular bacteria, such as Francisella tularensis, utilize the anti-inflammatory cytokine IL-10 to evade the host immune response, mainly by suppressing antigen presentation. 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 IL12p70 and TNFa, in an IFN-γ-dependent fashion. In addition, F. tularensis drives the alternative activation of alveolar macrophages at the early stages of infection, thus allowing the bacterium to avoid protective immunity. Furthermore, for the first time, we demonstrate that targeting inactivated F. tularensis (iFt) to Fcγ receptors via intranasal immunization with mAb-iFt complexes, 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 in the respiratory mucosa, as well as 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.