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A bacterial cyclic dinucleotide activates the cytosolic surveillance pathway and mediates innate resistance to tuberculosis
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A bacterial cyclic dinucleotide activates the cytosolic surveillance pathway and mediates innate resistance to tuberculosis
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Journal Article
A bacterial cyclic dinucleotide activates the cytosolic surveillance pathway and mediates innate resistance to tuberculosis
2015
Overview
William Bishai and colleagues report that cyclic-di-adenosine monophosphate produced during infection with
Mycobacterium tuberculosis
induces IFN-β and contributes to the innate sensing of tuberculosis.
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
1
,
2
,
3
. 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)
4
-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)
5
-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)
6
,
7
, 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.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
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/ Animals
/ Bacteria
/ Bacterial Proteins - metabolism
/ Dinucleoside Phosphates - metabolism
/ Female
/ Genetic Complementation Test
/ Interferon-beta - metabolism
/ Interferon-gamma - metabolism
/ letter
/ Mice
/ Nucleotidyltransferases - metabolism
/ Phosphorus-Oxygen Lyases - metabolism
