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Nat Med. 2015 Apr;21(4):401-6. doi: 10.1038/nm.3813. Epub 2015 Mar 2.

A bacterial cyclic dinucleotide activates the cytosolic surveillance pathway and mediates innate resistance to tuberculosis.

Author information

1
1] Center for Tuberculosis Research, Johns Hopkins University, Baltimore, Maryland, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
2
Center for Tuberculosis Research, Johns Hopkins University, Baltimore, Maryland, USA.
3
1] Center for Tuberculosis Research, Johns Hopkins University, Baltimore, Maryland, USA. [2] Department of Pediatrics, Johns Hopkins University, Baltimore, Maryland, USA.

Abstract

Detection of cyclic-di-adenosine monophosphate (c-di-AMP), a bacterial second messenger, by the host cytoplasmic surveillance pathway (CSP) is known to elicit type I interferon (IFN) responses, which are crucial to antimicrobial defense. However, the mechanisms and role of c-di-AMP signaling in Mycobacterium tuberculosis virulence remain unclear. Here we show that resistance to tuberculosis requires CSP-mediated detection of c-di-AMP produced by M. tuberculosis and that levels of c-di-AMP modulate the fate of infection. We found that a di-adenylate cyclase (disA or dacA)-overexpressing M. tuberculosis strain that secretes excess c-di-AMP activates the interferon regulatory factor (IRF) pathway with enhanced levels of IFN-β, elicits increased macrophage autophagy, and exhibits substantial virulence attenuation in mice. We show that c-di-AMP-mediated IFN-β induction during M. tuberculosis infection requires stimulator of interferon genes (STING)-signaling. We observed that c-di-AMP induction of IFN-β is independent of the cytosolic nucleic acid receptor cyclic GMP-AMP (cGAMP) synthase (cGAS), but cGAS nevertheless contributes substantially to the overall IFN-β response to M. tuberculosis infection. In sum, our results reveal c-di-AMP to be a key mycobacterial pathogen-associated molecular pattern (PAMP) driving host type I IFN responses and autophagy. These findings suggest that modulating the levels of this small molecule may lead to novel immunotherapeutic strategies against tuberculosis.

PMID:
25730264
PMCID:
PMC4390473
DOI:
10.1038/nm.3813
[Indexed for MEDLINE]
Free PMC Article

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