Streptococcus pneumoniae DNA Initiates Type I Interferon Signaling in the Respiratory Tract

Parker, Dane; Martin, Francis J.; Soong, Grace; Harfenist, Bryan S.; Aguilar, Jorge L.; Ratner, Adam J.; Fitzgerald, Katherine A.; Schindler, Christian; Prince, Alice

doi:10.1128/mbio.00016-11

Cited by 132 publications

(138 citation statements)

References 55 publications

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“…Alternatively, the aforementioned pathways could compensate for each other and mediate type I IFN induction during pneumococcal infection cooperatively. Our findings that the S. pneumoniae-stimulated type I IFN induction is dependent on PLY and on STING-mediated recognition of bacterial DNA are in agreement with a study that was published when our manuscript was under revision (55).…”

Section: Discussionsupporting

confidence: 81%

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

104

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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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Section: Discussionsupporting

confidence: 81%

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

104

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“…The defect in IFN-g production in MyD88-deficient mice is not as large as that observed in Nox2-deficient mice, suggesting that other pattern recognition receptors that do not signal through MyD88 may be important in the recognition of and response to S. pneumoniae. Other pattern recognition receptors have been shown to play important roles in host defense against this organism, including TLR9 (71,72), NLRP3 (73,74), NOD2 (75), and DAI (76). Pore formation by pneumolysin may enable bacterial components to enter host cells, thereby facilitating recognition of bacterial components by intracellular pathogen recognition receptors.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Interferon-γ Production by Neutrophils and Its Function duringStreptococcus pneumoniaePneumonia

Gomez

Yamada

Martin

et al. 2015

Am J Respir Cell Mol Biol

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Bacterial pneumonia is a common public health problem associated with significant mortality, morbidity, and cost. Neutrophils are usually the earliest leukocytes to respond to bacteria in the lungs. Neutrophils rapidly sequester in the pulmonary microvasculature and migrate into the lung parenchyma and alveolar spaces, where they perform numerous effector functions for host defense. Previous studies showed that migrated neutrophils produce IFN-g early during pneumonia induced by Streptococcus pneumoniae and that early production of IFN-g regulates bacterial clearance. IFN-g production by neutrophils requires Rac2, Hck/Lyn/Fgr Src family tyrosine kinases, and NADPH oxidase. Our current studies examined the mechanisms that regulate IFN-g production by lung neutrophils during acute S. pneumoniae pneumonia in mice and its function. We demonstrate that IFN-g production by neutrophils is a tightly regulated process that does not require IL-12. The adaptor molecule MyD88 is critical for IFN-g production by neutrophils. The guanine nucleotide exchange factor CalDAG-GEFI modulates IFN-g production. The CD11/CD18 complex, CD44, Toll-like receptors 2 and 4, TRIF, and Nrf2 are not required for IFN-g production by neutrophils. The recently described neutrophil-dendritic cell hybrid cell, identified by its expression of Ly6G and CD11c, is present at low numbers in pneumonic lungs and is not a source of IFN-g. IFN-g produced by neutrophils early during acute S. pneumoniae pneumonia induces transcription of target genes in the lungs, which are critical for host defense. These studies underline the complexity of the neutrophil responses during pneumonia in the acute inflammatory response and in subsequent resolution or initiation of immune responses.

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“…Similarly, pneumococcal DNA enters airway epithelial and dendritic cells in a PLY-dependent fashion and then stimulates type I IFN signaling. IFN-␣/␤ receptor null mice showed increased nasal colonization with S. pneumoniae, indicating a role for IFN signaling in the mucosal response to this pathogen (441).…”

Section: Other Pft Functions and Effectsmentioning

confidence: 99%

Role of Pore-Forming Toxins in Bacterial Infectious Diseases

Los

Randis

Aroian

et al. 2013

Microbiol Mol Biol Rev

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347

351

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SUMMARY Pore-forming toxins (PFTs) are the most common bacterial cytotoxic proteins and are required for virulence in a large number of important pathogens, including Streptococcus pneumoniae , group A and B streptococci, Staphylococcus aureus , Escherichia coli , and Mycobacterium tuberculosis . PFTs generally disrupt host cell membranes, but they can have additional effects independent of pore formation. Substantial effort has been devoted to understanding the molecular mechanisms underlying the functions of certain model PFTs. Likewise, specific host pathways mediating survival and immune responses in the face of toxin-mediated cellular damage have been delineated. However, less is known about the overall functions of PFTs during infection in vivo . This review focuses on common themes in the area of PFT biology, with an emphasis on studies addressing the roles of PFTs in in vivo and ex vivo models of colonization or infection. Common functions of PFTs include disruption of epithelial barrier function and evasion of host immune responses, which contribute to bacterial growth and spreading. The widespread nature of PFTs make this group of toxins an attractive target for the development of new virulence-targeted therapies that may have broad activity against human pathogens.

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Streptococcus pneumoniae DNA Initiates Type I Interferon Signaling in the Respiratory Tract

Cited by 132 publications

References 55 publications

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

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

Mechanisms of Interferon-γ Production by Neutrophils and Its Function duringStreptococcus pneumoniaePneumonia

Role of Pore-Forming Toxins in Bacterial Infectious Diseases

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