Inhibition of innate immune cytosolic surveillance by an M. tuberculosis phosphodiesterase

Nat Chem Biol. 2017 Feb;13(2):210-217. doi: 10.1038/nchembio.2254. Epub 2016 Dec 12.


Mycobacterium tuberculosis infection leads to cytosolic release of the bacterial cyclic dinucleotide (CDN) c-di-AMP and a host-generated CDN, cGAMP, both of which trigger type I interferon (IFN) expression in a STING-dependent manner. Here we report that M. tuberculosis has developed a mechanism to inhibit STING activation and the type I IFN response via the bacterial phosphodiesterase (PDE) CdnP, which mediates hydrolysis of both bacterial-derived c-di-AMP and host-derived cGAMP. Mutation of cdnP attenuates M. tuberculosis virulence, as does loss of a host CDN PDE known as ENPP1. CdnP is inhibited by both US Food and Drug Administration (FDA)-approved PDE inhibitors and nonhydrolyzable dinucleotide mimetics specifically designed to target the enzyme. These findings reveal a crucial role of CDN homeostasis in governing the outcome of M. tuberculosis infection as well as a unique mechanism of subversion of the host's cytosolic surveillance pathway (CSP) by a bacterial PDE that may serve as an attractive antimicrobial target.

Publication types

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

MeSH terms

  • 2',3'-Cyclic-Nucleotide Phosphodiesterases / metabolism*
  • Cytosol / immunology*
  • Cytosol / microbiology*
  • Immunity, Innate*
  • Mycobacterium tuberculosis / enzymology*


  • 2',3'-Cyclic-Nucleotide Phosphodiesterases

Associated data

  • PubChem-Substance/318835056
  • PubChem-Substance/318835062
  • PubChem-Substance/318835067
  • PubChem-Substance/318835072
  • PubChem-Substance/318835073
  • PubChem-Substance/318835074
  • PubChem-Substance/318835075
  • PubChem-Substance/318835076
  • PubChem-Substance/318835057
  • PubChem-Substance/318835058
  • PubChem-Substance/318835059
  • PubChem-Substance/318835060
  • PubChem-Substance/318835061
  • PubChem-Substance/318835063
  • PubChem-Substance/318835064
  • PubChem-Substance/318835065
  • PubChem-Substance/318835066
  • PubChem-Substance/318835068
  • PubChem-Substance/318835069
  • PubChem-Substance/318835070
  • PubChem-Substance/318835071