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: Research - peer-reviewArticle

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.

LanguageEnglish (US)
Pages210-217
Number of pages8
JournalNature Chemical Biology
Volume13
Issue number2
DOIs
StatePublished - Feb 1 2017

Fingerprint

Phosphoric Diester Hydrolases
Tuberculosis
Interferon Type I
cyclic guanosine monophosphate-adenosine monophosphate
cyclic diadenosine phosphate
Mycobacterium Infections
Phosphodiesterase Inhibitors
United States Food and Drug Administration
Mycobacterium tuberculosis
Virulence
Hydrolysis
Homeostasis
Mutation
Enzymes
Infection

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Inhibition of innate immune cytosolic surveillance by an M.Tuberculosis phosphodiesterase. / Dey, Ruchi Jain; Dey, Bappaditya; Zheng, Yue; Cheung, Laurene S.; Zhou, Jie; Sayre, David; Kumar, Pankaj; Guo, Haidan; Lamichhane, Gyanu; Sintim, Herman O.; Bishai, William R.

In: Nature Chemical Biology, Vol. 13, No. 2, 01.02.2017, p. 210-217.

Research output: Research - peer-reviewArticle

Dey, RJ, Dey, B, Zheng, Y, Cheung, LS, Zhou, J, Sayre, D, Kumar, P, Guo, H, Lamichhane, G, Sintim, HO & Bishai, WR 2017, 'Inhibition of innate immune cytosolic surveillance by an M.Tuberculosis phosphodiesterase' Nature Chemical Biology, vol 13, no. 2, pp. 210-217. DOI: 10.1038/nchembio.2254
Dey RJ, Dey B, Zheng Y, Cheung LS, Zhou J, Sayre D et al. Inhibition of innate immune cytosolic surveillance by an M.Tuberculosis phosphodiesterase. Nature Chemical Biology. 2017 Feb 1;13(2):210-217. Available from, DOI: 10.1038/nchembio.2254
Dey, Ruchi Jain ; Dey, Bappaditya ; Zheng, Yue ; Cheung, Laurene S. ; Zhou, Jie ; Sayre, David ; Kumar, Pankaj ; Guo, Haidan ; Lamichhane, Gyanu ; Sintim, Herman O. ; Bishai, William R./ Inhibition of innate immune cytosolic surveillance by an M.Tuberculosis phosphodiesterase. In: Nature Chemical Biology. 2017 ; Vol. 13, No. 2. pp. 210-217
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