Unique Roles for Streptococcus pneumoniae Phosphodiesterase 2 in Cyclic di-AMP Catabolism and Macrophage Responses

Wooten, Alicia K; Shenoy, A.T.; Arafa, E.I.; Akiyama, Hisashi; Martin, I.M.C.; Jones, Matthew R.; Quinton, Lee J.; Gummuluru, Suryaram; Bai, Guangchun; Mizgerd, Joseph P.

doi:10.3389/fimmu.2020.00554

Cited by 9 publications

(8 citation statements)

References 48 publications

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“…And phosphodiesterase 1 (Pde1) and Pde2 are responsible for the degrading of c-di-AMP ( 237 ). Pneumococci deficient in Pde2 led to increased concentrations of c-di-AMP in the mutant pneumococci and resulted in the hyperactivation of STING and excessive IFN-β expression, as well as rapid cytotoxicity ( 238 ). However, another study showed that cGAS-STING pathway had no contribution to the immune response against S. pneumoniae in mice and humans, although pneumococcal DNA could be detected by cGAS and then initiated type I IFN production through STING ( 207 ).…”

Section: Cgas-sting In Bacterial Infectious Diseasesmentioning

confidence: 99%

Function and regulation of cGAS-STING signaling in infectious diseases

Luo

et al. 2023

Front. Immunol.

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The efficacious detection of pathogens and prompt induction of innate immune signaling serve as a crucial component of immune defense against infectious pathogens. Over the past decade, DNA-sensing receptor cyclic GMP-AMP synthase (cGAS) and its downstream signaling adaptor stimulator of interferon genes (STING) have emerged as key mediators of type I interferon (IFN) and nuclear factor-κB (NF-κB) responses in health and infection diseases. Moreover, both cGAS-STING pathway and pathogens have developed delicate strategies to resist each other for their survival. The mechanistic and functional comprehension of the interplay between cGAS-STING pathway and pathogens is opening the way for the development and application of pharmacological agonists and antagonists in the treatment of infectious diseases. Here, we briefly review the current knowledge of DNA sensing through the cGAS-STING pathway, and emphatically highlight the potent undertaking of cGAS-STING signaling pathway in the host against infectious pathogenic organisms.

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Section: Cgas-sting In Bacterial Infectious Diseasesmentioning

confidence: 99%

Function and regulation of cGAS-STING signaling in infectious diseases

Luo

et al. 2023

Front. Immunol.

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“…However, crosstalk between c‐di‐AMP and (p)ppGpp has not been established in streptococci. Interestingly, deletion of gdpP in S. pneumoniae increased bacterial c‐di‐AMP levels when grown in broth culture but not on blood agar plates (Bai et al., 2013; Wooten et al., 2020), suggesting a differential regulation of GdpP or its activity between the culture conditions. Consistently, less induction of type I interferon by the gdpP mutant was detected compared to that by the pde2 mutant when both pneumococcal strains were collected from blood agar plates (Wooten et al., 2020).…”

Section: Degradation Of C‐di‐amp In Streptococcimentioning

confidence: 99%

“…Interestingly, deletion of gdpP in S. pneumoniae increased bacterial c‐di‐AMP levels when grown in broth culture but not on blood agar plates (Bai et al., 2013; Wooten et al., 2020), suggesting a differential regulation of GdpP or its activity between the culture conditions. Consistently, less induction of type I interferon by the gdpP mutant was detected compared to that by the pde2 mutant when both pneumococcal strains were collected from blood agar plates (Wooten et al., 2020). Furthermore, in a UV treatment assay using blood agar plates, the pneumococcal ∆ gdpP mutant exhibited 3‐ to 9‐fold more killing than the parental strain, whereas the ∆ pde2 mutant displayed over 100‐fold killing than the parental strain (Bai et al., 2013).…”

Section: Degradation Of C‐di‐amp In Streptococcimentioning

confidence: 99%

Bacterial second messenger cyclic di‐AMP in streptococci

Wright,

Bai

2023

Molecular Microbiology

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Cyclic dimeric adenosine monophosphate (c‐di‐AMP) has been well studied in bacteria, including those of the genus Streptococcus, since the first recognition of this dinucleotide in 2008. Streptococci possess a sole diadenylate cyclase, CdaA, and distinct c‐di‐AMP phosphodiesterases. Interestingly, cdaA is required for viability of some streptococcal species but not all when streptococci are grown in standard laboratory media. Bacteria of this genus also have distinct c‐di‐AMP effector proteins, diverse c‐di‐AMP‐signaling pathways, and subsequent biological outcomes. In streptococci, c‐di‐AMP may influence bacterial growth, morphology, biofilm formation, competence program, drug resistance, and bacterial pathogenesis. c‐di‐AMP secreted by streptococci has also been shown to interact with the mammalian host and induces immune responses including type I interferon production. In this review, we summarize the reported c‐di‐AMP networks in seven species of the genus Streptococcus, which cause diverse clinical manifestations, and propose future perspectives to investigate the signaling molecule in these streptococcal pathogens.

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“…It enters mature phagolysosomes and releases nucleic acids and c-di-AMP into the host cytosol via a secretion system or following partial lysis. S. pneumoniae c-di-AMP initiates host innate immune responses by activating STING directly and increasing the expression of IFN-β ( 99 ). IFN-β production is also induced by pneumolysin (Ply), a pore-forming protein and a major virulence factor of S. pneumoniae.…”

Section: Extracellular Gram-positive Bacteriamentioning

confidence: 99%

The cGAS-STING Pathway in Bacterial Infection and Bacterial Immunity

et al. 2022

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Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) synthase (cGAS), along with the adaptor stimulator of interferon genes (STING), are crucial components of the innate immune system, and their study has become a research hotspot in recent years. Many biochemical and structural studies that have collectively elucidated the mechanism of activation of the cGAS-STING pathway with atomic resolution have provided insights into the roles of the cGAS-STING pathway in innate immunity and clues to the origin and evolution of the modern cGAS-STING signaling pathway. The cGAS-STING pathway has been identified to protect the host against viral infection. After detecting viral dsDNA, cGAS synthesizes a second messenger to activate STING, eliciting antiviral immune responses by promoting the expression of interferons (IFNs) and hundreds of IFN-stimulated genes (ISGs). Recently, the cGAS-STING pathway has also been found to be involved in response to bacterial infections, including bacterial pneumonia, melioidosis, tuberculosis, and sepsis. However, compared with its functions in viral infection, the cGAS-STING signaling pathway in bacterial infection is more complex and diverse since the protective and detrimental effects of type I IFN (IFN-I) on the host depend on the bacterial species and infection mode. Besides, STING activation can also affect infection prognosis through other mechanisms in different bacterial infections, independent of the IFN-I response. Interestingly, the core protein components of the mammalian cGAS-STING signaling pathway have been found in the bacterial defense system, suggesting that this widespread signaling pathway may have originated in bacteria. Here, we review recent findings related to the structures of major molecules involved in the cGAS-STING pathway and the effects of the cGAS-STING pathway in various bacterial infections and bacterial immunity, which may pave the way for the development of new antibacterial drugs that specifically kill bacteria without harmful effects on the host.

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Unique Roles for Streptococcus pneumoniae Phosphodiesterase 2 in Cyclic di-AMP Catabolism and Macrophage Responses

Cited by 9 publications

References 48 publications

Function and regulation of cGAS-STING signaling in infectious diseases

Function and regulation of cGAS-STING signaling in infectious diseases

Bacterial second messenger cyclic di‐AMP in streptococci

The cGAS-STING Pathway in Bacterial Infection and Bacterial Immunity

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