Abstract
Francisella tularensis, the causative agent of tularemia, is one of the deadliest agents of biological warfare and bioterrorism. Extremely high virulence of this bacterium is associated with its ability to dampen or subvert host innate immune response. The objectives of this study were to identify factors and understand the mechanisms of host innate immune evasion by F. tularensis. We identified and explored the pathogenic role of a mutant interrupted at gene locus FTL_0325, which encodes an OmpA-like protein. Our results establish a pathogenic role of FTL_0325 and its ortholog FTT0831c in the virulent F. tularensis SchuS4 strain in intramacrophage survival and suppression of proinflammatory cytokine responses. This study provides mechanistic evidence that the suppressive effects on innate immune responses are due specifically to these proteins and that FTL_0325 and FTT0831c mediate immune subversion by interfering with NF-κB signaling. Furthermore, FTT0831c inhibits NF-κB activity primarily by preventing the nuclear translocation of p65 subunit. Collectively, this study reports a novel F. tularensis factor that is required for innate immune subversion caused by this deadly bacterium.
Highlights
The mechanism of immune suppression caused by Francisella tularensis SchuS4 strain, a category A agent, are yet unknown
We report that OmpA-like proteins encoded by FTL_0325/FTT0831c genes of F. tularensis live vaccine strain (LVS) and SchuS4 strains, respectively, are required for intramacrophage survival and suppression of proinflammatory cytokines
FTL_0325 Mutant of F. tularensis Induces Significantly Increased Proinflammatory Cytokines in Macrophages—In our transposon mutant screen, a mutant in FTL_0325 gene of F. tularensis was identified that exhibited a 7-fold reduction in the number of bacteria recovered at 24 h post-infection (PI) as compared with the Wild type (WT) F. tularensis
Summary
The mechanism of immune suppression caused by Francisella tularensis SchuS4 strain, a category A agent, are yet unknown. Results: FTL_0325/FTT0831c genes of F. tularensis suppress proinflammatory cytokines by preventing activation of NF-B signaling. The objectives of this study were to identify factors and understand the mechanisms of host innate immune evasion by F. tularensis. Our results establish a pathogenic role of FTL_0325 and its ortholog FTT0831c in the virulent F. tularensis SchuS4 strain in intramacrophage survival and suppression of proinflammatory cytokine responses. This study provides mechanistic evidence that the suppressive effects on innate immune responses are due to these proteins and that FTL_0325 and FTT0831c mediate immune subversion by interfering with NF-B signaling. This study reports a novel F. tularensis factor that is required for innate immune subversion caused by this deadly bacterium
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