Francisella gains a survival advantage within mononuclear phagocytes by suppressing the host IFNgamma response.
Tularemia is a zoonotic disease caused by the Gram-negative intracellular pathogen Francisella tularensis. These bacteria evade phagolysosomal fusion, escape from the phagosome and replicate in the host cell cytoplasm. IFNgamma has been shown to suppress the intra-macrophage growth of Francisella through both nitric oxide-dependent and -independent pathways. Since Francisella is known to subvert host immune responses, we hypothesized that this pathogen could interfere with IFNgamma signaling. Here, we report that infection with Francisella suppresses IFNgamma-induced STAT1 expression and phosphorylation in both human and murine mononuclear phagocytes. This suppressive effect of Francisella is independent of phagosomal escape or replication and is mediated by a heat-stable and constitutively expressed bacterial factor. An analysis of the molecular mechanism of STAT1 inhibition indicated that expression of SOCS3, an established negative regulator of IFNgamma signaling, is highly up-regulated during infection and suppresses STAT1 phosphorylation. Functional analyses revealed that this interference with IFNgamma signaling is accompanied by the suppression of IP-10 production and iNOS induction resulting in increased intracellular bacterial survival. Importantly, the suppressive effect on IFNgamma-mediated host cell protection is most effective when IFNgamma is added post infection, suggesting that the bacteria establish a permissive environment within the host cell.
Parsa
Kishore V L
KV
The Ohio State Biochemistry Program, The Ohio State University, Columbus, OH 43210, USA.
Butchar
Jonathan P
JP
Rajaram
Murugesan V S
MV
Cremer
Thomas J
TJ
Gunn
John S
JS
Schlesinger
Larry S
LS
Tridandapani
Susheela
S
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D005604:Francisella tularensis / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology* / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000382:microbiology; D051379:Mice; D050296:Microbial Viability / Q000187:drug effects / Q000276:immunology*; D018448:Models, Immunological; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010586:Phagocytes / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology*; D010588:Phagosomes / Q000187:drug effects / Q000382:microbiology; D010766:Phosphorylation / Q000187:drug effects; D050794:STAT1 Transcription Factor / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D014406:Tularemia / Q000276:immunology / Q000382:microbiology
D050794:STAT1 Transcription Factor; C491411:Socs3 protein, mouse; C494080:Stat1 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D009569:Nitric Oxide; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II