Identification of a novel Francisella tularensis factor required for intramacrophage survival and subversion of innate immune response.
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.
Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York 12208, USA.
Manish
M
Mahawar
Maninjay K
MK
Atianand
Rachel J
RJ
Dotson
Vanessa
V
Mora
Seham M
SM
Rabadi
Dennis W
DW
Metzger
Jason F
JF
Huntley
Jonathan A
JA
Harton
Meenakshi
M
Malik
Chandra Shekhar
CS
Bakshi
D000818:Animals; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D005604:Francisella tularensis / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity*; D056426:Genetic Loci / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051996:Transcription Factor RelA / Q000235:genetics / Q000276:immunology; D014406:Tularemia / Q000235:genetics / Q000276:immunology*; D037521:Virulence Factors / Q000235:genetics / Q000276:immunology*
D001425:Bacterial Outer Membrane Proteins; C498143:RELA protein, human; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D037521:Virulence Factors