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

Ruchi Jain Dey, Bappaditya Dey, Yue Zheng, Laurene S. Cheung, Jie Zhou, David Sayre, Pankaj Kumar, Haidan Guo, Gyanu Lamichhane, Herman O. Sintim, William R. Bishai

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)210-217
Number of pages8
JournalNature chemical biology
Issue number2
StatePublished - Feb 1 2017

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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