The cGAS/STING Pathway Detects Streptococcus pneumoniae but Appears Dispensable for Antipneumococcal Defense in Mice and Humans

Ruiz-Moreno, Juan Sebastián; Hamann, Lutz; Jin, Lei; Sander, Leif E.; Puzianowska-Kuźnicka, Monika; Cambier, John C.; Witzenrath, Martin; Schumann, Ralf R.; Suttorp, Norbert; Opitz, Bastian

doi:10.1128/iai.00849-17

Cited by 20 publications

(18 citation statements)

References 63 publications

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“…Recognition by DNA sensors is a prerequisite for triggering type I IFN response, in which cGAS has a critical role. It has also been reported that cGAS is involved in the expression of IFN-b mediated by S. pn or mtDNA [15,36]. We found that STING deletion impaired the expression of Ply-induced type I IFNs, and we detected increased phosphorylation of the STING downstream element IRF3.…”

Section: Discussionsupporting

confidence: 77%

Type I IFN expression is stimulated by cytosolic MtDNA released from pneumolysin‐damaged mitochondria via the STING signaling pathway in macrophages

Peng

et al. 2019

The FEBS Journal

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Pneumolysin (Ply), a major virulence factor of Streptococcus pneumoniae (S. pn), affects the immunity of host cells during infection. It has been reported that Ply is involved in S. pn standard strain D39‐induced interferon‐β (IFN‐β) expression; however, other findings suggest that recombinant Ply protein is incapable of triggering IFN‐β expression. Here, we demonstrated that purified Ply was capable of initiating oxidative damage to mitochondria, resulting in the subsequent release of mitochondrial deoxyribonucleic acid (mtDNA), which mediated IFN‐β expression in macrophages. Importantly, we determined that IFN‐β expression was regulated by stimulator of interferon genes (STING) signaling in response to Ply. In conclusion, our study identified that IFN‐β production was triggered by Ply in macrophages and mtDNA released from Ply‐damaged mitochondria mediated this process, through the STING pathway. This is a novel mechanism by which S. pn modulates type I IFN response in macrophages.

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Section: Discussionsupporting

confidence: 77%

Type I IFN expression is stimulated by cytosolic MtDNA released from pneumolysin‐damaged mitochondria via the STING signaling pathway in macrophages

Peng

et al. 2019

The FEBS Journal

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“…To investigate if pneumococcal c-di-AMP could be a modulator of type I interferon responses, RAW264.7 macrophage-like cells were infected with the phosphodiesterase mutants and mRNA was collected so that IFNβ expression could be measured. We expected one of three outcomes: consistently elevated IFNβ responses across the mutant pneumococci, matching the observations with NF-κB activity ( Figure 1); a ramping up of IFNβ responses with peak levels after infection by the double mutant pde1 pde2 strain, based on how c-di-AMP content in pneumococci increase due to phosphodiesterase mutations (26); or no effect of phosphodiesterase mutation, based on the postulate that pneumococcal DNA but not c-di-AMP drives IFNβ responses (19). Surprisingly, macrophage IFNβ responses matched none of these expectations.…”

Section: Mixed Macrophage Ifnβ Responses To the Phosphodiesterase Mutmentioning

confidence: 55%

“…STING is an adaptor molecule and receptor for cyclic dinucleotides in the cytosol including the bacterial metabolites cyclic di-GMP and cyclic di-AMP (c-di-AMP), as well as the mammalian-derived cyclic GMP-AMP (cGAMP) produced by the cyclic GMP-AMP synthase (cGAS) enzyme (16)(17)(18). Induction of IFNβ by pneumococcus requires both STING and cGAS (19), which was interpreted as evidence that pneumococcal DNA but not pneumococcal c-di-AMP triggers STING-dependent IFNβ induction (19). However, a cGAS-STING complex is essential to IFNβ induction by purified c-di-AMP (20), which could contribute to the requirement for cGAS in pneumococcus-induced signaling.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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Cyclic di-AMP (c-di-AMP) is an important signaling molecule for pneumococci, and as a uniquely prokaryotic product it can be recognized by mammalian cells as a danger signal that triggers innate immunity. Roles of c-di-AMP in directing host responses during pneumococcal infection are only beginning to be defined. We hypothesized that pneumococci with defective c-di-AMP catabolism due to phosphodiesterase deletions could illuminate roles of c-di-AMP in mediating host responses to pneumococcal infection. Pneumococci deficient in phosphodiesterase 2 (Pde2) stimulated a rapid induction of interferon β (IFNβ) expression that was exaggerated in comparison to that induced by wild type (WT) bacteria or bacteria deficient in phosphodiesterase 1. This IFNβ burst was elicited in mouse and human macrophage-like cell lines as well as in primary alveolar macrophages collected from mice with pneumococcal pneumonia. Macrophage hyperactivation by Pde2-deficient pneumococci led to rapid cell death. STING and cGAS were essential for the excessive IFNβ induction, which also required phagocytosis of bacteria and triggered the phosphorylation of IRF3 and IRF7 transcription factors. The select effects of Pde2 deletion were products of a unique role of this enzyme in c-di-AMP catabolism when pneumococci were grown on solid substrate conditions designed to enhance virulence. Because pneumococci with elevated c-di-AMP drive aberrant innate immune responses from macrophages involving hyperactivation of STING, excessive IFNβ expression, and rapid cytotoxicity, we surmise that c-di-AMP is pivotal for directing innate immunity and host-pathogen interactions during pneumococcal pneumonia.

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“…Immune Cells Homozygous for STING-R231H but Not STING-HAQ Respond to Endogenous 2 ′ 3 ′ cGAMP STING plays a central role in intracellular DNA sensing pathways by binding the cGAS product 2 ′ 3 ′ cGAMP, resulting in IRF3 activation. Previous work suggested that STING-HAQ is a null allele, disabling the carrier's ability to respond to 2 ′ 3 ′ cGAMP (29), although others have reported residual ability of PBMCs of STING-HAQ/HAQ carriers to respond to intracellular DNA or cGAMP (38,39). We incubated heterozygous and homozygous STING-HAQ B cells with increasing concentrations of 2 ′ 3 ′ cGAMP.…”

Section: Heterozygous Sting-haq B Cells and Sting-r231h B Cells Have mentioning

confidence: 99%

Selective Loss of Responsiveness to Exogenous but Not Endogenous Cyclic-Dinucleotides in Mice Expressing STING-R231H

et al. 2020

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Stimulator of interferon genes (STING) plays a central role in innate immune responses to viral and intracellular bacterial infections, and cellular damage. STING is a cytosolic sensor of cyclic dinucleotides (CDNs) including those produced by pathogenic bacteria and those arising endogenously as products of the DNA sensor cGAS (e.g., 2 ′ 3 ′ cGAMP). The two most common alternative allelic variants of STING in humans are STING-R71H-G230A-R293Q (STING-HAQ) and STING-R232H that are found in 20.4% and 13.7-17.6% of the population, respectively. To determine the biologic consequences of these genotypic variations, we generated knock-in mice containing the murine equivalents of each variant and studied their responsiveness to CDNs. Homozygous STING-HAQ (R71H-I229A-R292Q) and STING-R231H mice were found to be unresponsive to all exogenous CDNs tested (ci-di-GMP, ci-di-AMP, 3 ′ 3 ′ cGAMP and Rp,Rp-CDA). Responses of homozygous STING-HAQ mice to endogenous 2 ′ 3 ′ cGAMP was also greatly impaired. However, homozygous STING-R231H mice are fully responsive to 2 ′ 3 ′ cGAMP. Analysis of heterozygous mice revealed reduced responsiveness to exogenous and endogenous CDNs in mice carrying a single copy of STING-HAQ, while STING-R231H heterozygous mice exhibit reduced responsiveness to exogenous but not endogenous CDNs. These findings confirm and extend previous reports by demonstrating differing impact of allelic variation of STING on the ability to sense and respond to exogenous vs. endogenous CDNs. Finally, the STING-R231H variant mouse represents a useful tool with which to examine the relative contributions of STING sensing of exogenous and endogenous CDNs in the context of bacterial infections and CDN-based cancer immunotherapeutics.

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The cGAS/STING Pathway Detects Streptococcus pneumoniae but Appears Dispensable for Antipneumococcal Defense in Mice and Humans

Cited by 20 publications

References 63 publications

Type I IFN expression is stimulated by cytosolic MtDNA released from pneumolysin‐damaged mitochondria via the STING signaling pathway in macrophages

Type I IFN expression is stimulated by cytosolic MtDNA released from pneumolysin‐damaged mitochondria via the STING signaling pathway in macrophages

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

Selective Loss of Responsiveness to Exogenous but Not Endogenous Cyclic-Dinucleotides in Mice Expressing STING-R231H

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