title: Inhibition of innate immune cytosolic surveillance by an M. tuberculosis phosphodiesterase.
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.
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University, Baltimore, Maryland, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Ruchi Jain
authors.initials: RJ
authors.lastname: Dey
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University, Baltimore, Maryland, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Bappaditya
authors.initials: B
authors.lastname: Dey
authors.affiliation: Department of Chemistry &Biochemistry, University of Maryland, College Park, Maryland, USA.|Department of Chemistry and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Laurene S
authors.initials: LS
authors.lastname: Cheung
authors.affiliation: Department of Chemistry &Biochemistry, University of Maryland, College Park, Maryland, USA.|Department of Chemistry and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Chemistry &Biochemistry, University of Maryland, College Park, Maryland, USA.
authors.forename: David
authors.initials: D
authors.lastname: Sayre
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Haidan
authors.initials: H
authors.lastname: Guo
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Gyanu
authors.initials: G
authors.lastname: Lamichhane
authors.affiliation: Department of Chemistry &Biochemistry, University of Maryland, College Park, Maryland, USA.|Department of Chemistry and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana, USA.|Purdue Institute of Inflammation, Immunology and Infectious Disease, West Lafayette, Indiana, USA.
authors.forename: Herman O
authors.initials: HO
authors.lastname: Sintim
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University, Baltimore, Maryland, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Bishai
mesh_terms: D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000378:metabolism*; D003600:Cytosol / Q000276:immunology* / Q000382:microbiology*; D007113:Immunity, Innate; D009169:Mycobacterium tuberculosis / Q000201:enzymology*
chemical_list: D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases