2. Academic Validation
  3. Inhibition of innate immune cytosolic surveillance by an M. tuberculosis phosphodiesterase

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.
Ruchi Jain Dey 1 2,  Bappaditya Dey 1 2,  Yue Zheng 3 4,  Laurene S Cheung 1,  Jie Zhou 3 4,  David Sayre 3,  Pankaj Kumar 1,  Haidan Guo 1,  Gyanu Lamichhane 1,  Herman O Sintim 3 4 5,  William R Bishai 1 2
Affiliations

Affiliations

  • 1 Center for Tuberculosis Research, Johns Hopkins University, Baltimore, Maryland, USA.
  • 2 Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
  • 3 Department of Chemistry &Biochemistry, University of Maryland, College Park, Maryland, USA.
  • 4 Department of Chemistry and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana, USA.
  • 5 Purdue Institute of Inflammation, Immunology and Infectious Disease, West Lafayette, Indiana, USA.
PMID: 28106876 DOI: 10.1038/nchembio.2254
Abstract

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.

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