A host type I interferon response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-GMP

McWhirter, Sarah M.; Barbalat, Roman; Monroe, Kathryn M.; Fontana, Mary F.; Hyodo, Mamoru; Joncker, Nathalie T.; Ishii, Ken J.; Akira, Shizuo; Colonna, Marco; Chen, Zhijian J.; Fitzgerald, Katherine A.; Hayakawa, Yoshihiro; Vance, Russell E.

doi:10.1084/jem.20082874

Cited by 269 publications

(313 citation statements)

References 62 publications

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“…8). Alternatively, like other intracellular pathogens, it is possible that many chlamydial compounds, ranging from metabolites to bacterial RNAs, leak into the cytoplasm and are sensed by pattern recognition receptors (71,72) and that cPLA 2 plays a role in their recognition by modulating bacterial or inclusion membrane stability.…”

Section: Discussionmentioning

confidence: 99%

cPLA2 Regulates the Expression of Type I Interferons and Intracellular Immunity to Chlamydia trachomatis

Vignola

Kashatus

Taylor

et al. 2010

Journal of Biological Chemistry

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Infection with the obligate bacterial intracellular pathogenChlamydia trachomatis leads to the sustained activation of the small GTPase RAS and many of its downstream signaling components. In particular, the mitogen-activated protein kinase ERK and the calcium-dependent phospholipase cPLA 2 are activated and are important for the onset of inflammatory responses. In this study we tested if activation of ERK and cPLA 2 occurred as a result of RAS signaling during infection and determined the relative contribution of these signaling components to chlamydial replication and survival. We provide genetic and pharmacological evidence that during infection RAS, ERK, and, to a lesser extent, cPLA 2 activation are uncoupled, suggesting that Chlamydia activates individual components of this signaling pathway in a non-canonical manner. In human cell lines, inhibition of ERK or cPLA 2 signaling did not adversely impact C. trachomatis replication. In contrast, in murine cells, inhibition of ERK and cPLA 2 played a significant protective role against C. trachomatis. We determined that cPLA 2 -deficient murine cells are permissive for C. trachomatis replication because of their impaired expression of ␤ interferon and the induction of immunity-related GTPases (IRG) important for the containment of intracellular pathogens. Furthermore, the MAPK p38 was primarily responsible for cPLA 2 activation in Chlamydia-infected cells and IRG expression. Overall, these findings define a previously unrecognized role for cPLA 2 in the induction of cell autonomous cellular immunity to Chlamydia and highlight the many non-canonical signaling pathways engaged during infection.

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Section: Discussionmentioning

confidence: 99%

cPLA2 Regulates the Expression of Type I Interferons and Intracellular Immunity to Chlamydia trachomatis

Vignola

Kashatus

Taylor

et al. 2010

Journal of Biological Chemistry

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“…C-di-GMP contains two phosphate groups and this prevents it from passing through the cell membrane, even though the target molecule of c-di-GMP is located in the cytoplasm [24]. Clearly, a suitable drug delivery system (DDS) is needed to permit c-di-GMP to penetrate the cell membrane and pass into the cytoplasmic region, if it is to be used as an adjuvant.…”

Section: Introductionmentioning

confidence: 99%

A new adjuvant delivery system ‘cyclic di-GMP/YSK05 liposome’ for cancer immunotherapy

Miyabe

Hyodo

Nakamura

et al. 2014

Journal of Controlled Release

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140

108

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Cyclic dinucleotides are of importance in the field of microbiology and immunology. They function as second messengers and are thought to participate in the signal transduction of cytosolic DNA immune responses. One such dinucleotide, cyclic di-GMP (c-di-GMP), stimulates the immune system. C-di-GMP is thought to be recognized by ATP dependant RNA helicase (DDX41) in the cytosol, forms a complex with the Stimulator of interferon genes protein (STING), triggers the signal via the tank binding kinase 1 -interferon regulatory factor 3 (TBK1-IRF3) pathway and induces the production of type I interferons. Therefore c-di-GMP can be thought of as a new class of adjuvant. However, because c-di-GMP contains two phosphate groups, this prevents its use as the adjuvant because it cannot pass through the cell membrane, even though the target molecule of c-di-GMP is located in the cytoplasm.Our group have been developing a series of liposomal drug delivery systems and recently investigated YSK05 which is a synthetic lipid with a pH sensitivity and has a high fusogenicity. We utilized this lipid as a carrier to send c-di-GMP into the cytosol to then use c-di-GMP as an adjuvant. Based on screening experiments, YSK05/POPE/Cholesterol = 40/30/30 was found to induce IFN-β in Raw264.7 cells. The induction of IFN-β from c-di-GMP liposomes was inhibited by adding BX795, a TBK1 inhibitor, indicating that the production of IFN-β caused the activation of STING-TBK1 pathway. C-di-GMP liposomes also showed significantly higher levels of expression of CD80, CD86 and MHC class I. The c-di-GMP/YSK05 liposome facilitated antigen specific cytotoxic T cell activity and the inhibition of tumor growth in a mouse model. These findings indicate that c-di-GMP/YSK05 liposomes could be used, not only to transfer c-di-GMP to the cytosol and induce an innate immune system but also as a platform for investigating the mechanism of immune sensing with cyclic dinucleotides in vitro and in vivo.

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“…Although DAI/ZBP1, RNA PolIII-RIG-I, and IFN, g-inducible protein 16 (IFI16) have been identified as cytosolic DNA sensors (25)(26)(27)(28), their roles in most bacterial infections remain to be characterized. Moreover, cytosolic sensing of RNA by RLRs and cyclic dinucleotides by a yet-to-be-identified receptor has also been implicated in some bacteria-induced type I IFN responses (29)(30)(31). Most of these sensing pathways appear to signal via the adapter molecule STING, the kinase TBK1, and the transcription factor IFN regulatory factor 3 (IRF3) (23,32,33).…”

mentioning

confidence: 99%

Streptococcus pneumoniaeStimulates a STING- and IFN Regulatory Factor 3-Dependent Type I IFN Production in Macrophages, which Regulates RANTES Production in Macrophages, Cocultured Alveolar Epithelial Cells, and Mouse Lungs

Koppe

Högner

Doehn

et al. 2012

The Journal of Immunology

108

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Streptococcus pneumoniae is the leading cause of community-acquired pneumonia. In this study, we examine an innate immune recognition pathway that senses pneumococcal infection, triggers type I IFN production, and regulates RANTES production. We found that human and murine alveolar macrophages as well as murine bone marrow macrophages, but not alveolar epithelial cells, produced type I IFNs upon infection with S. pneumoniae. This response was dependent on the pore-forming toxin pneumolysin and appeared to be mediated by a cytosolic DNA-sensing pathway involving the adapter molecule STING and the transcription factor IFN regulatory factor 3. Indeed, DNA was present in the cytosol during pneumococcal infection as indicated by the activation of the AIM2 inflammasome, which is known to sense microbial DNA. Type I IFNs produced by S. pneumoniae-infected macrophages positively regulated gene expression and RANTES production in macrophages and cocultured alveolar epithelial cells in vitro. Moreover, type I IFNs controlled RANTES production during pneumococcal pneumonia in vivo. In conclusion, we identified an immune sensing pathway detecting S. pneumoniae that triggers a type I IFN response and positively regulates RANTES production.

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A host type I interferon response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-GMP

Cited by 269 publications

References 62 publications

cPLA2 Regulates the Expression of Type I Interferons and Intracellular Immunity to Chlamydia trachomatis

cPLA2 Regulates the Expression of Type I Interferons and Intracellular Immunity to Chlamydia trachomatis

A new adjuvant delivery system ‘cyclic di-GMP/YSK05 liposome’ for cancer immunotherapy

Streptococcus pneumoniaeStimulates a STING- and IFN Regulatory Factor 3-Dependent Type I IFN Production in Macrophages, which Regulates RANTES Production in Macrophages, Cocultured Alveolar Epithelial Cells, and Mouse Lungs

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