Dissection of a type I interferon pathway in controlling bacterial intracellular infection in mice

Lippmann, Juliane; Müller, HC; Naujoks, Jan; Tabeling, Christoph; Shin, Sunny; Witzenrath, Martin; Hellwig, Katharina; Kirschning, Carsten J.; Taylor, Gregory A.; Barchet, Winfried; Bauer, Stefan; Suttorp, Norbert; Roy, Craig R.; Opitz, Bastian

doi:10.1111/j.1462-5822.2011.01646.x

Cited by 75 publications

(86 citation statements)

References 66 publications

(128 reference statements)

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“…Furthermore, type I IFN-␣ receptor-deficient (IFNAR Ϫ/Ϫ ) macrophages were more permissive to L. pneumophila infection in vitro than were wild-type cells (11). There was no difference in bacterial detection in the lungs when IFNAR2 Ϫ/Ϫ and wild-type mice were compared 48 h after L. pneumophila infection (12), nor was there a difference in lung bacterial burden between wild-type and IFNAR Ϫ/Ϫ mice (13). Despite this, most reports suggest that type I IFN supports cellular resistance to L. pneumophila infection.…”

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confidence: 87%

Type I Interferon Counters or Promotes Coxiella burnetii Replication Dependent on Tissue

et al. 2016

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Coxiella burnetii is an intracellular pathogen and the cause of Q fever. Gamma interferon (IFN-␥) is critical for host protection from infection, but a role for type I IFN in C. burnetii infection has not been determined. Type I IFN supports host protection from a related pathogen, Legionella pneumophila, and we hypothesized that it would be similarly protective in C. burnetii infection. In contrast to our prediction, IFN-␣ receptor-deficient (IFNAR ؊/؊ ) mice were protected from C. burnetii-induced infection. Therefore, the role of type I IFN in C. burnetii infection was distinct from that in L. pneumophila. Mice treated with a double-stranded-RNA mimetic were protected from C. burnetii-induced weight loss through an IFNAR-independent pathway. We next treated mice with recombinant IFN-␣ (rIFN-␣). When rIFN-␣ was injected by the intraperitoneal route during infection, disease-induced weight loss was exacerbated. Mice that received rIFN-␣ by this route had dampened interleukin 1␤ (IL-1␤) expression in bronchoalveolar lavage fluids. However, when rIFN-␣ was delivered to the lung, bacterial replication was decreased in all tissues. Thus, the presence of type I IFN in the lung protected from infection, but when delivered to the periphery, type I IFN enhanced disease, potentially by dampening inflammatory cytokines. To better characterize the capacity for type I IFN induction by C. burnetii, we assessed expression of IFN-␤ transcripts by human macrophages following stimulation with lipopolysaccharide (LPS) from C. burnetii. Understanding innate responses in C. burnetii infection will support the discovery of novel therapies that may be alternative or complementary to the current antibiotic treatment.

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confidence: 87%

Type I Interferon Counters or Promotes Coxiella burnetii Replication Dependent on Tissue

et al. 2016

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“…The induction of type I IFNs is regulated in part by extracellular sensors, such as TLR4, as well as cytosolic sensors, such as the RNA sensors RIG-I and MDA-5, the DNA sensor cGAS, and the cyclic dinucleotide sensor STING (103)(104)(105). Type I IFNs are elicited during L. pneumophila infection and aid in restricting intracellular bacterial replication (67)(68)(69)(70)(106)(107)(108) Fig. 5A and B).…”

Section: To E) Tlr2mentioning

confidence: 99%

“…Whereas A/J macrophages are permissive for L. pneumophila replication, C57BL/6 macrophages restrict L. pneumophila replication (64). Studying how C57BL/6 macrophages sense and control L. pneumophila infection has allowed for the identification of multiple TLR-and cytosolic PRR-mediated responses involved in this process, such as the NAIP5 inflammasome and the proinflammatory cytokines TNF and type I IFNs (20,(65)(66)(67)(68)(69)(70). Importantly, the activation of cytosolic PRRs involves the sensing of bacterial products, such as flagellin, that are translocated into the host cell cytosol by a functional L. pneumophila Dot/Icm T4SS (71,72).…”

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confidence: 99%

Primary Role for Toll-Like Receptor-Driven Tumor Necrosis Factor Rather than Cytosolic Immune Detection in Restricting Coxiella burnetii Phase II Replication within Mouse Macrophages

et al. 2016

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dCoxiella burnetii replicates within permissive host cells by employing a Dot/Icm type IV secretion system (T4SS) to translocate effector proteins that direct the formation of a parasitophorous vacuole. C57BL/6 mouse macrophages restrict the intracellular replication of the C. burnetii Nine Mile phase II (NMII) strain. However, eliminating Toll-like receptor 2 (TLR2) permits bacterial replication, indicating that the restriction of bacterial replication is immune mediated. Here, we examined whether additional innate immune pathways are employed by C57BL/6 macrophages to sense and restrict NMII replication. In addition to the known role of TLR2 in detecting and restricting NMII infection, we found that TLR4 also contributes to cytokine responses but is not required to restrict bacterial replication. Furthermore, the TLR signaling adaptors MyD88 and Trif are required for cytokine responses and restricting bacterial replication. The C. burnetii NMII T4SS translocates bacterial products into C57BL/6 macrophages. However, there was little evidence of cytosolic immune sensing of NMII, as there was a lack of inflammasome activation, T4SS-dependent cytokine responses, and robust type I interferon (IFN) production, and these pathways were not required to restrict bacterial replication. Instead, endogenous tumor necrosis factor (TNF) produced upon TLR sensing of C. burnetii NMII was required to control bacterial replication. Therefore, our findings indicate a primary role for TNF produced upon immune detection of C. burnetii NMII by TLRs, rather than cytosolic PRRs, in enabling C57BL/6 macrophages to restrict bacterial replication.T o initiate innate immune defense against bacterial pathogens, infected host cells utilize pattern recognition receptors (PRRs) to detect pathogen-associated molecular patterns (PAMPs) (1-3). Toll-like receptors (TLRs) located at the cell surface and within endosomes detect extracellular PAMPs such as bacterial lipoproteins and lipopolysaccharide (LPS) (4). Downstream of TLRs, the adaptor proteins MyD88 and Trif activate several signaling pathways, including NF-B, mitogen-activated protein kinases (MAPKs), and interferon (IFN) regulatory factor 3 (IRF3), which direct the expression of proinflammatory cytokines and other antimicrobial effectors (4). For intracellular bacterial pathogens, cytosolic PRRs, such as those of the nucleotide binding domain/ leucine-rich repeat (NLR) and RIG-I-like receptor (RLR) families, often are critical for host defense as they respond to PAMPs introduced into the host cell cytosol by bacterial pore-forming toxins or specialized secretion systems (5-8). In addition, cytosolic sensing can lead to the assembly of a multiprotein complex termed the inflammasome, which activates the host proteases caspase-1 and caspase-11, resulting in the release of IL-1 family cytokines and a form of cell death known as pyroptosis (9-16). These innate immune pathways collaborate to restrict intracellular bacterial infection through both cell-intrinsic and -extrinsic mechanisms (17)(18...

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“…A number of studies demonstrated that bacteria-infected cells produce IFN-b (16)(17)(18)(19)(20)(21)(22)(23)(24). In several infection models, this response has been indicated to depend on cytosolic sensing of bacterial DNA.…”

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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

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Högner

Doehn

et al. 2012

The Journal of Immunology

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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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Dissection of a type I interferon pathway in controlling bacterial intracellular infection in mice

Cited by 75 publications

References 66 publications

Type I Interferon Counters or Promotes Coxiella burnetii Replication Dependent on Tissue

Type I Interferon Counters or Promotes Coxiella burnetii Replication Dependent on Tissue

Primary Role for Toll-Like Receptor-Driven Tumor Necrosis Factor Rather than Cytosolic Immune Detection in Restricting Coxiella burnetii Phase II Replication within Mouse Macrophages

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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