Mycobacterium tuberculosis Triggers Host Type I IFN Signaling To Regulate IL-1 Production in Human Macrophages

Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
The Journal of Immunology (Impact Factor: 4.92). 09/2011; 187(5):2540-7. DOI: 10.4049/jimmunol.1100926
Source: PubMed


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.

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Available from: Katrin D Mayer-Barber, May 28, 2014
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    • "Similarly, type I IFN production was associated with reduced secretion of IL-12 and TNFα in both L. monocytogenes and M. tuberculosis infection models (68, 72). Type I IFNs also suppress IL-1β production by inhibiting inflammasome activation (97), and reduced IL-1β secretion correlated with increased host susceptibility in M. tuberculosis infection models (98, 99). Expression of chemokines such as CCL2 is also regulated by type I IFNs (100, 101). "
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    • "Recent data suggested IL-1β may be downregulated by type I IFN in human monocytic cells in vitro. [47] However, it is not clear why IL1B would be downregulated by IFN in EBV but upregulated by IFN in most other viral infections. Another possibility was suggested by a recent report, which showed that EBV encodes a microRNA (BART15) that targets the NLRP3 inflammasome, and exosome mediated secretion of this miRNA resulted in downregulation of IL-1β in bystander (uninfected) monocytes in vitro. "
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    • "tuberculosis) is an intracellular respiratory bacterium that replicates primarily within macrophages and dendritic cells, before forming latent granulomas in the infected organs [33], and is the causative agent of tuberculosis (TB). We found no evidence for control of M. tuberculosis bacterial growth in murine lungs, despite the fact that the pathogen triggers a type I IFN response [34], which subsequently up-regulates Ifitm3 expression. Further, a recent study implicated a SNP (rs3888188) in the promoter of IFITM3 with susceptibility to TB [21], wherein the minority rs3888188-G allele was significantly overrepresented in patients with TB compared to healthy controls in a Han Chinese population. "
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