Mycobacterium tuberculosis triggers host type I IFN signaling to regulate IL-1β production in human macrophages

Aleksey Novikov, Marco Cardone, Robert Thompson, Kevin Shenderov, Kevin D. Kirschman, Katrin D. Mayer-Barber, Timothy G. Myers, Ronald L. Rabin, Giorgio Trinchieri, Alan Sher, Carl G. Feng

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2540-2547
Number of pages8
JournalJournal of Immunology
Volume187
Issue number5
DOIs
StatePublished - Sep 1 2011
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Novikov, A., Cardone, M., Thompson, R., Shenderov, K., Kirschman, K. D., Mayer-Barber, K. D., Myers, T. G., Rabin, R. L., Trinchieri, G., Sher, A., & Feng, C. G. (2011). Mycobacterium tuberculosis triggers host type I IFN signaling to regulate IL-1β production in human macrophages. Journal of Immunology, 187(5), 2540-2547. https://doi.org/10.4049/jimmunol.1100926