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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy
  • Bacterial Proteins / metabolism*
  • Cytokines / metabolism
  • Cytosol / metabolism*
  • Dinucleoside Phosphates / metabolism*
  • Female
  • Genetic Complementation Test
  • Interferon-beta / metabolism
  • Interferon-gamma / metabolism
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mycobacterium tuberculosis
  • Nucleotidyltransferases / metabolism
  • Phosphorus-Oxygen Lyases / metabolism*
  • Signal Transduction
  • Tuberculosis / metabolism*
  • Tuberculosis / prevention & control
  • Virulence


  • Bacterial Proteins
  • Cytokines
  • Dinucleoside Phosphates
  • Interferon-beta
  • Interferon-gamma
  • Nucleotidyltransferases
  • cGAS protein, mouse
  • Phosphorus-Oxygen Lyases