Francisella gains a survival advantage within mononuclear phagocytes by suppressing the host IFNγ response
| Autor: | John S. Gunn, Thomas J. Cremer, Larry S. Schlesinger, Susheela Tridandapani, Jonathan P. Butchar, Murugesan V. S. Rajaram, Kishore V. L. Parsa |
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| Rok vydání: | 2008 |
| Předmět: |
Immunology
Nitric Oxide Synthase Type II Suppressor of Cytokine Signaling Proteins Nitric Oxide Monocytes Article Cell Line Microbiology Tularemia Interferon-gamma Mice Immune system Phagosomes medicine Animals Humans SOCS3 Phosphorylation Francisella tularensis Molecular Biology Cell Proliferation Phagosome Phagocytes Microbial Viability biology Macrophages Models Immunological biology.organism_classification medicine.disease STAT1 Transcription Factor Suppressor of Cytokine Signaling 3 Protein Host cell cytoplasm Leukocytes Mononuclear bacteria Francisella Intracellular |
| Zdroj: | Molecular Immunology. 45:3428-3437 |
| ISSN: | 0161-5890 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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