Recognition of Coxiella burnetii by Toll-like Receptors and Nucleotide-Binding Oligomerization Domain-like Receptors

Ammerdorffer, Anne; Schoffelen, Teske; Gresnigt, Mark S.; Oosting, Marije; Brok, Martijn H. den; Abdollahi‐Roodsaz, Shahla; Kanneganti, Thirumala‐Devi; Jong, Dirk J. de; Deuren, Marcel van; Roest, Hendrik Jan; Rebel, J.M.J.; Netea, Mihai G.; Joosten, Leo A. B.; Sprong, Tom

doi:10.1093/infdis/jiu526

Cited by 25 publications

(42 citation statements)

References 34 publications

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“…C57BL/6 (B6) bone marrow-derived macrophages (BMDMs) do not permit the robust intracellular replication of C. burnetii NMII (56). Restriction of NMII replication is mediated in part by TLR2 signaling (58), and TLR2 is required for the production of proinflammatory cytokines by human PBMCs in response to C. burnetii phase I infection and mouse macrophages in response to both C. burnetii phase I and phase II (58,61). However, the roles of other TLRs or the signaling adaptor MyD88 or Trif in enabling B6 macrophages to restrict NMII replication or mount an effective cytokine response are largely unknown.…”

Section: Resultsmentioning

confidence: 99%

“…C. burnetii lipid A is thought to be poorly stimulatory for TLR4 and is capable of behaving as a TLR4 antagonist in human PBMCs (58). Abolishing TLR4 alone does not impact cytokine responses to phase I or II infection in vitro, and the absence of TLR4 does not affect NMII replication within mouse macrophages (58,61). Given that TLR2 responds so robustly to NMII, we wondered whether a role for TLR4 could be revealed in the absence of TLR2.…”

Section: Resultsmentioning

confidence: 99%

“…L. pneumophila induces rapid p38 MAPK activation within 20 min postinfection that involves both TLR signaling as well as cytosolic sensing of T4SS-translocated bacterial effectors (89,90). p38 MAPK activation contributes to cytokine production in cells infected with C. burnetii phase I or phase II (61,(91)(92)(93), but whether p38 MAPK activation involves TLR or cytosolic sensing of C. burnetii is unknown. To test if p38 MAPK phosphorylation shortly after C. burnetii NMII infection requires TLR signaling, we infected B6 and Myd88 Ϫ/Ϫ BMDMs with NMII and examined p38 MAPK phosphorylation up to 2 h postinfection (Fig.…”

Section: To E) Tlr2mentioning

confidence: 99%

“…Furthermore, C. burnetii NMII can translocate type 4 secretion system (T4SS) effectors into C57BL/6 macrophages (59), indicating that the block in bacterial replication is due to intracellular PRR sensing of T4SS-translocated products. Indeed, the cytosolic sensor NOD2 contributes to cytokine responses against C. burnetii phase I organisms, demonstrating the potential for C. burnetii to be detected by cytosolic surveillance pathways (60,61). Whether cytosolic immune pathways detect and restrict C. burnetii NMII infection in B6 macrophages is not known.…”

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confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: To E) Tlr2mentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…We observed similar results with in vitro infection of peritoneal and pulmonary macrophages (data not shown). Also, recently it has been shown that TLR1/ TLR2 in human cells can be an important recognition receptor for C. burnetii infection, leading to robust cytokine responses (36). Therefore, the absence of TLR2 signaling may allow for the development of permissive populations of macrophages for C. burnetii growth.…”

Section: Discussionmentioning

confidence: 99%

Roles of Toll-Like Receptor 2 (TLR2), TLR4, and MyD88 during Pulmonary Coxiella burnetii Infection

et al. 2016

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Coxiella burnetii, the causative agent of Q fever, is an obligate intracellular, primarily pulmonary, bacterial pathogen. Although much is known about adaptive immune responses against this bacterium, our understanding of innate immune responses against C. burnetii is not well defined, particularly within the target tissue for infection, the lung. Previous studies examined the roles of the innate immune system receptors Toll-like receptor 2 (TLR2) and TLR4 in peripheral infection models and described minimal phenotypes in specific gene deletion animals compared to those of their wild-type controls ( Here, we assessed the roles for TLR2, TLR4, and MyD88 in pulmonary C. burnetii infection and compared responses to those that occurred in TLR2-and TLR4-deficient animals following peripheral infection. As observed previously, neither TLR2 nor TLR4 was needed for limiting bacterial growth after peripheral infection. In contrast, TLR2 and, to a lesser extent, TLR4 limited growth (or dissemination) of the bacterium in the lung and spleen after pulmonary infection. TLR2, TLR4, and MyD88 were not required for the general inflammatory response in the lungs after pulmonary infection. However, MyD88 signaling was important for infection-induced morbidity. Finally, TLR2 expression on hematopoietic cells was most important for limiting bacterial growth in the lung. These results expand on our knowledge of the roles for TLR2 and TLR4 in C. burnetii infection and suggest various roles for these receptors that are dictated by the site of infection.

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Immune Responses to Bacterial Infections

2020

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Recognition of Coxiella burnetii by Toll-like Receptors and Nucleotide-Binding Oligomerization Domain-like Receptors

Abstract: The TLR1/TLR2 heterodimer and NOD2 are important recognition receptors for the induction of cytokine responses against C. burnetii in humans. Furthermore, an interesting finding was the divergent recognition of C. burnetii Nine Mile and C. burnetii 3262.

Cited by 25 publications

References 34 publications

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

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

Roles of Toll-Like Receptor 2 (TLR2), TLR4, and MyD88 during Pulmonary Coxiella burnetii Infection

Immune Responses to Bacterial Infections

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