Lipopolysaccharide Preparation Extracted from<i>Porphyromonas gingivalis</i>Lipoprotein-Deficient Mutant Shows a Marked Decrease in Toll-Like Receptor 2-Mediated Signaling

Asai, Yasuyuki; Hashimoto, Masahito; Fletcher, Hansel M.; Miyake, Kensuke; Akira, Shizuo; Ogawa, Tomohiko

doi:10.1128/iai.73.4.2157-2163.2005

Cited by 50 publications

(49 citation statements)

References 46 publications

(46 reference statements)

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“…Absence of endotoxin was further confirmed by LAL assay (Lonza). None of the dilutions tested generated a positive LAL reaction at an assay sensitivity of 0.03 EU/ml (data not shown) (6,11,48). The native fimbria was further analyzed by TEM, demonstrating the presence of oligomeric strands approximately 100 to 200 nm in length, which is similar to previous observations (41) (Fig.…”

Section: Resultssupporting

confidence: 73%

The Native 67-Kilodalton Minor Fimbria of Porphyromonas gingivalis Is a Novel Glycoprotein with DC-SIGN-Targeting Motifs

et al. 2010

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Section: Resultssupporting

confidence: 73%

The Native 67-Kilodalton Minor Fimbria of Porphyromonas gingivalis Is a Novel Glycoprotein with DC-SIGN-Targeting Motifs

et al. 2010

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“…Other reports, however, describe P. gingivalis LPS preparations as a highly heterogeneous mixture of different types of lipid A species with differential levels of stimulatory potency in their effects on TLR2 and TLR4 (10,14,49). In addition, a few studies demonstrated that TLR2 activity can be attributed to P. gingivalis lipoproteins (50)(51)(52). However, since methods that are more refined than the SDS-PAGE performed in this study (see Fig.…”

Section: Discussionmentioning

confidence: 55%

Porphyromonas gingivalis Outer Membrane Vesicles Induce Selective Tumor Necrosis Factor Tolerance in a Toll-Like Receptor 4- and mTOR-Dependent Manner

et al. 2016

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f Porphyromonas gingivalis is an important member of the anaerobic oral flora. Its presence fosters growth of periodontal biofilm and development of periodontitis. In this study, we demonstrated that lipophilic outer membrane vesicles (OMV) shed from P. gingivalis promote monocyte unresponsiveness to live P. gingivalis but retain reactivity to stimulation with bacterial DNA isolated from P. gingivalis or AIM2 ligand poly(dA·dT). OMV-mediated tolerance of P. gingivalis is characterized by selective abrogation of tumor necrosis factor (TNF). Neutralization of interleukin-10 (IL-10) during OMV challenge partially restores monocyte responsiveness to P. gingivalis; full reactivity to P. gingivalis can be restored by inhibition of mTOR signaling, which we previously identified as the major signaling pathway promoting Toll-like receptor 2 and Toll-like receptor 4 (TLR2/4)-mediated tolerance in monocytes. However, despite previous reports emphasizing a central role of TLR2 in innate immune recognition of P. gingivalis, our current findings highlight a selective role of TLR4 in the promotion of OMV-mediated TNF tolerance: only blockade of TLR4 -and not of TLR2-restores responsiveness to P. gingivalis. Of further note, OMV-mediated tolerance is preserved in the presence of cytochalasin B and chloroquine, indicating that triggering of surface TLR4 is sufficient for this effect. Taking the results together, we propose that P. gingivalis OMV contribute to local immune evasion of P. gingivalis by hampering the host response. P eriodontitis (PD) is probably the most frequent chronic inflammatory disorder associated with an alteration of the local microbiota. Clinically, release of inflammatory mediators induces collagen degradation and bone resorption, which ultimately result in tooth loss. The carbohydrate-deficient subgingival environment fosters the growth of Porphyromonas gingivalis (1). Tissue degradation caused by enzymes released from bacteria and neutrophils provokes an inflammatory response and supplies bacteria with additional nutrients. This specific milieu permits growth of P. gingivalis, whose sophisticated mechanisms for immune evasion enhance growth of the periodontal biofilm, thus leading to bacterial overgrowth and excessive immune stimulation (2, 3).P. gingivalis releases outer membrane lipophilic microvesicles, which contain lipopolysaccharide (LPS) as a major structural component (4-6). These outer membrane vesicles (OMV) overcome the epithelial barrier, thus transporting LPS and other virulence factors into the host tissue (7). Subsequently, OMV elicit a robust mucosal immune response (8), an effect exploited in OMV-based vaccines (8, 9) and mainly attributed to their LPS content (6). However, unlike LPS from Escherichia coli or Salmonella spp., which are Toll-like receptor 4 (TLR4) agonists, P. gingivalis LPS contains a mixture of chemically diverse lipid A species with distinct immune stimulatory properties (10). Albeit P. gingivalis LPS was formerly thought to act as a TLR2 ligand (11, 12), recent studi...

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“…Adding weight to this hypothesis, and similar to observations made with E. coli LPS preparations (32,33), a lipoprotein with TLR2 agonist activity was identified from P. gingivalis LPS preparations (34). A mutant lacking this lipoprotein, PG1828, rendered its LPS attenuated for TLR2 activation (35).…”

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confidence: 69%

A Novel Class of Lipoprotein Lipase-Sensitive Molecules Mediates Toll-Like Receptor 2 Activation by Porphyromonas gingivalis

et al. 2013

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Infection by the chronic periodontitis-associated pathogen Porphyromonas gingivalis activates a Toll-like receptor 2 (TLR2) response that triggers inflammation in the host but also promotes bacterial persistence. Our aim was to define ligands on the surfaces of intact P. gingivalis cells that determine its ability to activate TLR2. Molecules previously reported as TLR2 agonists include lipopolysaccharide (LPS), fimbriae, the lipoprotein PG1828, and phosphoceramides. We demonstrate that these molecules do not comprise the major factors responsible for stimulating TLR2 by whole bacterial cells. First, P. gingivalis mutants devoid of the reported protein agonists, PG1828 and fimbriae, activate TLR2 as strongly as the wild type. Second, two-phase extraction of whole bacteria resulted in a preponderance of TLR2 agonist activity partitioning to the hydrophilic phase, demonstrating that phosphoceramides are not a major TLR2 ligand. Third, analysis of LPS revealed that TLR2 activation is independent of lipid A structural variants. Instead, activation of TLR2 and TLR2/TLR1 by LPS is in large part due to copurifying molecules that are sensitive to the action of the enzyme lipoprotein lipase. Strikingly, intact P. gingivalis bacterial cells treated with lipoprotein lipase were attenuated in their ability to activate TLR2. We propose that a novel class of molecules comprised by lipoproteins constitutes the major determinants that confer to P. gingivalis the ability to stimulate TLR2 signaling. Porphyromonas gingivalis is a Gram-negative anaerobic bacterium associated with chronic periodontitis, an inflammatory disease that results in tooth loss (1). P. gingivalis is typically found in diseased subgingival sites (2). Mouse models of P. gingivalis infection have demonstrated its capacity to elicit periodontitis, as measured by bone loss (3-5). A recent study revealed a key role played by P. gingivalis infection in altering the composition, and increasing the abundance, of oral commensal bacteria in conventionally grown mice (4). The interaction between an increasing bacterial load and the host innate immune system triggers a proinflammatory response, which is considered a major factor in causing periodontitis.The Toll-like receptor (TLR) family of innate immune receptors plays a pivotal role in host surveillance and in initiating an immediate immune response that is designed to neutralize microbial threats to the host (6). P. gingivalis infection triggers activation of TLR2, which leads to production of proinflammatory cytokines. One impact of these cytokines is a damaging effect on alveolar bone, resulting in bone loss, as demonstrated by studies using TLR2 Ϫ/Ϫ mice (3, 7). Paradoxically, the robust TLR2 proinflammatory response does not clear P. gingivalis infection in wild-type mice. Instead, the infection is cleared more efficiently in TLR2 Ϫ/Ϫ mice and by macrophages from TLR2 Ϫ/Ϫ mice (3, 5, 7), indicating that TLR2 stimulation confers enhanced persistence to this chronic pathogen. A lack of bacterial clearance illustra...

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Lipopolysaccharide Preparation Extracted fromPorphyromonas gingivalisLipoprotein-Deficient Mutant Shows a Marked Decrease in Toll-Like Receptor 2-Mediated Signaling

Cited by 50 publications

References 46 publications

The Native 67-Kilodalton Minor Fimbria of Porphyromonas gingivalis Is a Novel Glycoprotein with DC-SIGN-Targeting Motifs

The Native 67-Kilodalton Minor Fimbria of Porphyromonas gingivalis Is a Novel Glycoprotein with DC-SIGN-Targeting Motifs

Porphyromonas gingivalis Outer Membrane Vesicles Induce Selective Tumor Necrosis Factor Tolerance in a Toll-Like Receptor 4- and mTOR-Dependent Manner

A Novel Class of Lipoprotein Lipase-Sensitive Molecules Mediates Toll-Like Receptor 2 Activation by Porphyromonas gingivalis

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