Identification of a <i>Mycobacterium tuberculosis</i> Cyclic Dinucleotide Phosphodiesterase Inhibitor

Karanja, Caroline; Yeboah, Kofi S.; Sintim, Herman O.

doi:10.1021/acsinfecdis.0c00444

Cited by 9 publications

(10 citation statements)

References 33 publications

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“…A similar case has been reported for another pro-virulent cyclic nucleotide phosphodiesterase of Mycobacterium tuberculosis encoded by the Rv2837c [or cnpB ( Yang et al, 2014 )] gene, which, although incidentally named also CdnP, like the S. agalactiae protein, is not a metallophos/5_nucleotid_C but a DHH-DHHA1 domain, a soluble protein with an unclear outward/inward orientation in M. tuberculosis membrane ( Manikandan et al, 2014 ; He et al, 2016 ; Dey et al, 2017 ; Li, 2017 ). The bacterial stratagem of interfering with innate immunity by the hydrolysis of cyclic dinucleotides makes these enzymes interesting targets to develop novel therapeutic strategies in infectious diseases ( Andrade et al, 2016 ; Dey et al, 2017 ; Li, 2017 ; Devaux et al, 2018 ; Eaglesham and Kranzusch, 2020 ; Karanja et al, 2021 ; López-Villamizar et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Enzyme Characterization of Pro-virulent SntA, a Cell Wall-Anchored Protein of Streptococcus suis, With Phosphodiesterase Activity on cyclic-di-AMP at a Level Suited to Limit the Innate Immune System

et al. 2022

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Streptococcus suis and Streptococcus agalactiae evade the innate immune system of the infected host by mechanisms mediated by cell wall-anchored proteins: SntA and CdnP, respectively. The former has been reported to interfere with complement responses, and the latter dampens STING-dependent type-I interferon (IFN) response by hydrolysis of bacterial cyclic-di-AMP (c-di-AMP). Both proteins are homologous but, while CdnP has been studied as a phosphohydrolase, the enzyme activities of SntA have not been investigated. The core structure of SntA was expressed in Escherichia coli as a GST-tagged protein that, after affinity purification, was characterized as phosphohydrolase with a large series of substrates. This included 3′-nucleotides, 2′,3′-cyclic nucleotides, cyclic and linear dinucleotides, and a variety of phosphoanhydride or phosphodiester compounds, most of them previously considered as substrates of E. coli CpdB, a periplasmic protein homologous to SntA and CdnP. Catalytic efficiency was determined for each SntA substrate, either by dividing parameters kcat/KM obtained from saturation curves or directly from initial rates at low substrate concentrations when saturation curves could not be obtained. SntA is concluded to act as phosphohydrolase on two groups of substrates with efficiencies higher or lower than ≈ 105 M–1 s–1 (average value of the enzyme universe). The group with kcat/KM ≥ 105 M–1 s–1 (good substrates) includes 3′-nucleotides, 2′,3′-cyclic nucleotides, and linear and cyclic dinucleotides (notably c-di-AMP). Compounds showing efficiencies <104 M–1 s–1 are considered poor substrates. Compared with CpdB, SntA is more efficient with its good substrates and less efficient with its poor substrates; therefore, the specificity of SntA is more restrictive. The efficiency of the SntA activity on c-di-AMP is comparable with the activity of CdnP that dampens type-I IFN response, suggesting that this virulence mechanism is also functional in S. suis. SntA modeling revealed that Y530 and Y633 form a sandwich with the nitrogen base of nucleotidic ligands in the substrate-binding site. Mutants Y530A-SntA, Y633A-SntA, and Y530A+Y633A-SntA were obtained and kinetically characterized. For orientation toward the catalytic site, one tyrosine is enough, although this may depend on the substrate being attacked. On the other hand, both tyrosines are required for the efficient binding of good SntA substrates.

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Section: Introductionmentioning

confidence: 99%

Enzyme Characterization of Pro-virulent SntA, a Cell Wall-Anchored Protein of Streptococcus suis, With Phosphodiesterase Activity on cyclic-di-AMP at a Level Suited to Limit the Innate Immune System

et al. 2022

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“…Re-engineered BCG overexpressing c-di-AMP augmented trained immunity and exhibited improved efficacy against bladder cancer ( Singh et al, 2022 ). In addition, small molecules have been designed to modulate the cyclic dinucleotide-cGAS-STING axis ( Sintim et al, 2019 ), and inhibitors targeting M. tuberculosis cyclic dinucleotide phosphodiesterase have been identified in the regulation of the innate immune system ( Karanja et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

The role of bacterial cyclic di-adenosine monophosphate in the host immune response

Cheng

Jia

et al. 2022

Front. Microbiol.

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Cyclic di-adenosine monophosphate (c-di-AMP) is a second messenger which is widely used in signal transduction in bacteria and archaea. c-di-AMP plays an important role in the regulation of bacterial physiological activities, such as the cell cycle, cell wall stability, environmental stress response, and biofilm formation. Moreover, c-di-AMP produced by pathogens can be recognized by host cells for the activation of innate immune responses. It can induce type I interferon (IFN) response in a stimulator of interferon genes (STING)-dependent manner, activate the nuclear factor kappa B (NF-κB) pathway, inflammasome, and host autophagy, and promote the production and secretion of cytokines. In addition, c-di-AMP is capable of triggering a host mucosal immune response as a mucosal adjuvant. Therefore, c-di-AMP is now considered to be a new pathogen-associated molecular pattern in host immunity and has become a promising target in bacterial/viral vaccine and drug research. In this review, we discussed the crosstalk between bacteria and host immunity mediated by c-di-AMP and addressed the role of c-di-AMP as a mucosal adjuvant in boosting evoked immune responses of subunit vaccines. The potential application of c-di-AMP in immunomodulation and immunotherapy was also discussed in this review.

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“…However, the reason for the reduction of pulmonary immune cells in this study still needed to be further explored. C-di-AMP secreted by M. tuberculosis directly binds and activates STING molecules on the endoplasmic reticulum, thereby inducing a type I IFN immune response (Karanja et al, 2021). At the same time, the exogenous double-stranded DNA produced by M. tuberculosis is recognized by cyclic guanosine monophosphate/adenosine monophosphate synthase (cGAS) in host cells to generate endogenous cGAMP, which binds and activates the STING inducing a type I IFN immune response through transcription factor IRF3 (Cohen et al, 2019;Perez et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Cyclic-di-AMP Phosphodiesterase Elicits Protective Immune Responses Against Mycobacterium tuberculosis H37Ra Infection in Mice

Ning²,

Kang³

et al. 2022

Front. Cell. Infect. Microbiol.

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Many antigens from Mycobacterium tuberculosis (M. tuberculosis) have been demonstrated as strong immunogens and proved to have application potential as vaccine candidate antigens. Cyclic di-AMP (c-di-AMP) as a bacterial second messenger regulates various bacterial processes as well as the host immune responses. Rv2837c, the c-di-AMP phosphodiesterase (CnpB), was found to be relative to virulence of M. tuberculosis and interference with host innate immune response. In this study, recombinant CnpB was administered subcutaneously to mice. We found that CnpB had strong immunogenicity and induced high levels of humoral response and lung mucosal immunity after M. tuberculosis intranasally infection. CnpB immunization stimulated splenocyte proliferation and the increasing number of activated NK cells but had little effects on Th1/Th2 cellular immune responses in spleens. However, CnpB induced significant Th1/Th2 cellular immune responses with a decreased number of T and B cells in the lungs, and significantly recruits of CD4+ and CD8+ T cells after M. tuberculosis attenuated strain H37Ra infection. Besides, we first reported that CnpB could stimulate IFN-β expression transitorily and inhibit the autophagy of macrophages in vitro. In mice intranasally infection model, CnpB immunization alleviated pathological changes and reduced M. tuberculosis H37Ra loads in the lungs. Thus, our results suggested that CnpB interferes with host innate and adaptive immune responses and confers protection against M. tuberculosis respiratory infection, which should be considered in vaccine development as well as a drug target.

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Identification of a Mycobacterium tuberculosis Cyclic Dinucleotide Phosphodiesterase Inhibitor

Cited by 9 publications

References 33 publications

Enzyme Characterization of Pro-virulent SntA, a Cell Wall-Anchored Protein of Streptococcus suis, With Phosphodiesterase Activity on cyclic-di-AMP at a Level Suited to Limit the Innate Immune System

Enzyme Characterization of Pro-virulent SntA, a Cell Wall-Anchored Protein of Streptococcus suis, With Phosphodiesterase Activity on cyclic-di-AMP at a Level Suited to Limit the Innate Immune System

The role of bacterial cyclic di-adenosine monophosphate in the host immune response

Cyclic-di-AMP Phosphodiesterase Elicits Protective Immune Responses Against Mycobacterium tuberculosis H37Ra Infection in Mice

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