title: IFN-β mediates suppression of IL-12p40 in human dendritic cells following infection with virulent Francisella tularensis.
abstract: Active suppression of inflammation is a strategy used by many viral and bacterial pathogens, including virulent strains of the bacterium Francisella tularensis, to enable colonization and infection in susceptible hosts. In this study, we demonstrated that virulent F. tularensis strain SchuS4 selectively inhibits production of IL-12p40 in primary human cells via induction of IFN-β. In contrast to the attenuated live vaccine strain, infection of human dendritic cells with virulent SchuS4 failed to induce production of many cytokines associated with inflammation (e.g., TNF-α and IL-12p40). Furthermore, SchuS4 actively suppressed secretion of these cytokines. Assessment of changes in the expression of host genes associated with suppression of inflammatory responses revealed that SchuS4, but not live vaccine strain, induced IFN-β following infection of human dendritic cells. Phagocytosis of SchuS4 and endosomal acidification were required for induction of IFN-β. Further, using a defined mutant of SchuS4, we demonstrated that the presence of bacteria in the cytosol was required, but not sufficient, for induction of IFN-β. Surprisingly, unlike previous reports, induction of IFN-β by F. tularensis was not required for activation of the inflammasome, was not associated with exacerbation of inflammatory responses, and did not control SchuS4 replication when added exogenously. Rather, IFN-β selectively suppressed the ability of SchuS4-infected dendritic cells to produce IL-12p40. Together, these data demonstrated a novel mechanism by which virulent bacteria, in contrast to attenuated strains, modulate human cells to cause disease.
authors.affiliation: Immunity to Pulmonary Pathogens Section, Laboratory of Intracellular Parasites/Rocky Mountain Laboratories/National Institute of Allergy and Infectious Disease/National Institutes of Health, Hamilton, MT 59840, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Bauler
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Chase
authors.forename: Catharine M
authors.initials: CM
authors.lastname: Bosio
mesh_terms: D001428:Bacterial Vaccines / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D005604:Francisella tularensis / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes / Q000276:immunology* / Q000378:metabolism; D016899:Interferon-beta / Q000096:biosynthesis / Q000276:immunology*; D053762:Interleukin-12 Subunit p40 / Q000096:biosynthesis / Q000276:immunology*; D010587:Phagocytosis / Q000276:immunology; D014406:Tularemia / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology; D014613:Vaccines, Attenuated / Q000276:immunology / Q000378:metabolism
chemical_list: D001428:Bacterial Vaccines; C500879:IL12B protein, human; D058847:Inflammasomes; D053762:Interleukin-12 Subunit p40; D014409:Tumor Necrosis Factor-alpha; D014613:Vaccines, Attenuated; D016899:Interferon-beta