Understanding the role of FTT0831c encoded protein of F. tularensis in modulation of macrophage function (117.15)

Abstract

Abstract Francisella tularensis (Ft), a category A select agent, cripples innate immune defenses of the host to create an environment permissive for its growth. The objective of this study was to understand the mechanisms of innate immune evasion by Ft LVS (Type B) and the highly virulent SchuS4 (Type A) strain. We report that proteins encoded by FTL_0325/FTT0831c genes of Ft LVS and SchuS4 strains respectively, are required for intramacrophage survival, virulence and suppression of proinflammatory cytokines. Our in vitro studies showed that over-expression of FTT0831c suppressed the canonical NF-κB pathway by inhibiting nuclear translocation of the p65 protein resulting in blockade of NF-κB-dependent activation of proinflammatory cytokines. Further studies showed that FTL_0325/FTT0831c gene products are also required for suppression of caspase-1 activation and secretion of IL-1β and IL-18. In conclusion, this study establishes FTL_0325/FTT0831c of Francisella as a key virulence factor that functions as immunosuppressant to facilitate bacterial persistence. Suppression of key signaling pathways via FTT0831c by virulent F. tularensis SchuS4 explains one of the mechanisms adopted by this pathogen to down-modulate the host’s innate immune response.