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.