Induction of lipoxin A4 by Francisella tularensis: a mechanism for regulation of pro-inflammatory responses during early-phase tularemia (INM3P.401)

Abstract

Abstract During respiratory tularemia, caused by inhalation of Francisella tularensis (Ft), we postulate that bacteria establish a principally anti-inflammatory environment and subvert host cell death programs to facilitate their unfettered replication within various cell types. Here we have explored the role of lipid mediators such as lipoxin A4 (LXA4) and prostaglandin E2 (PGE2) in host inflammatory responses manifested early during infection with Ft. An inverse relationship was observed between the production of LXA4 and PGE2 suggesting that Ft induces the generation of these eicosanoids to modulate cell death and enhance its own survival. This notion is supported by our findings that Ft triggers the release of LXA4, which inhibits apoptosis of macrophages. We also have elucidated the course of tularemia in mice deficient for 5-lipoxygenase (5-LO), leaving them incapable of generating LXA4, and observed elevated levels of PGE2, increased apoptosis, increased neutrophil recruitment and elevated release of pro-inflammatory cytokines and chemokines as compared to their wild-type counterparts. 5-LO deficient mice also were found to be less susceptible to lethal doses of Ft LVS as compared to wild-type mice. Our results suggests that 5-LO activity increases susceptibility to Ft infection, suggesting that targeting this pathway may have therapeutic benefit by limiting bacterial growth in tularemic individuals and perhaps those infected with other virulent respiratory pathogens.