title: Mycobacterium tuberculosis triggers host type I IFN signaling to regulate IL-1β production in human macrophages.
abstract: Mycobacterium tuberculosis is a virulent intracellular pathogen that survives in macrophages even in the presence of an intact adaptive immune response. Type I IFNs have been shown to exacerbate tuberculosis in mice and to be associated with disease progression in infected humans. Nevertheless, the mechanisms by which type I IFNs regulate the host response to M. tuberculosis infection are poorly understood. In this study, we show that M. tuberculosis induces an IFN-related gene expression signature in infected primary human macrophages, which is dependent on host type I IFN signaling as well as the mycobacterial virulence factor, region of difference-1. We further demonstrate that type I IFNs selectively limit the production of IL-1β, a critical mediator of immunity to M. tuberculosis. This regulation occurs at the level of IL1B mRNA expression, rather than caspase-1 activation or autocrine IL-1 amplification and appears to be preferentially used by virulent mycobacteria since avirulent M. bovis bacillus Calmette-Guérin (BCG) fails to trigger significant expression of type I IFNs or release of mature IL-1β protein. The latter property is associated with decreased caspase-1-dependent IL-1β maturation in the BCG-infected macrophages. Interestingly, human monocytes in contrast to macrophages produce comparable levels of IL-1β in response to either M. tuberculosis or BCG. Taken together, these findings demonstrate that virulent and avirulent mycobacteria employ distinct pathways for regulating IL-1β production in human macrophages and reveal that in the case of M. tuberculosis infection the induction of type I IFNs is a major mechanism used for this purpose.
authors.affiliation: Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Aleksey
authors.initials: A
authors.lastname: Novikov
authors.forename: Marco
authors.initials: M
authors.lastname: Cardone
authors.forename: Robert
authors.initials: R
authors.lastname: Thompson
authors.forename: Kevin
authors.initials: K
authors.lastname: Shenderov
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Kirschman
authors.forename: Katrin D
authors.initials: KD
authors.lastname: Mayer-Barber
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Myers
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Rabin
authors.forename: Giorgio
authors.initials: G
authors.lastname: Trinchieri
authors.forename: Alan
authors.initials: A
authors.lastname: Sher
authors.forename: Carl G
authors.initials: CG
authors.lastname: Feng
mesh_terms: D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007370:Interferon Type I / Q000276:immunology* / Q000378:metabolism; D053583:Interleukin-1beta / Q000096:biosynthesis*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000472:pathogenicity*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D007370:Interferon Type I; D053583:Interleukin-1beta