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

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

in 2',3'-Cyclic-Nucleotide Phosphodiesterases - metabolism / 631/250/255 / 631/326/41 / 631/80/86 / 631/92/610 / AMP / Antiinfectives and antibacterials / Bacteria / Biochemical Engineering / Biochemistry / Bioorganic Chemistry / Cell Biology / Chemistry / Chemistry/Food Science / Cytosol - immunology / Cytosol - microbiology / Enzymes / Homeostasis / Hydrolysis / Immunity, Innate / Inhibitors / Interferon / Mutation / Mycobacterium tuberculosis / Mycobacterium tuberculosis - enzymology / Phosphodiesterase / Signal transduction / Surveillance / Tuberculosis / Virulence

2017

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

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

2017

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

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

2017

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Journal Article

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

Zhou, Jie,

Sayre, David,

Cheung, Laurene S,

Kumar, Pankaj,

Dey, Ruchi Jain,

Zheng, Yue,

Sintim, Herman O,

Dey, Bappaditya,

Lamichhane, Gyanu,

Bishai, William R,

Guo, Haidan

2017

Overview

A mycobacterial phosphodiesterase, CdnP, hydrolyzes bacteria-derived 3′,5′-c-di-AMP as well as host-generated 2′,3′-cGAMP, which activates the host cytosolic surveillance pathway, to dampen host responses. 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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Publisher

Nature Publishing Group US,Nature Publishing Group

Subject

2',3'-Cyclic-Nucleotide Phosphodiesterases - metabolism

/ AMP

/ Antiinfectives and antibacterials