Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A phenotype-driven approach led to the first understanding of precisely what the Toll-like receptors (TLR) did, when it was determined that the mammalian endotoxin (lipopolysaccharide; LPS) receptor is encoded by TLR4. The TLRs are the primary sensors of the innate immune system, and without them, small inocula of microorganisms pose a major threat to the host, growing unchecked for a long period before they are recognized. Mutations that affect innate immune sensing may account for a substantial fraction of sepsis, and a highly significant excess of mutations in TLR4 has been identified in patients with systemic meningococcal disease. As such, it is important to understand the pathways that are responsible for innate immune sensing, including the signaling intermediates utilized by the TLRs. Random germline mutagenesis identified a locus, Lps2, which is required for normal responses to double-stranded RNA and LPS. Hence, a single transducer was found to serve both the TLR3 and TLR4 response pathways. The Lps2 mutation was found to ablate entirely the MyD88-independent pathway for LPS sensing, indicating that two and only two branches of the LPS sensing pathway exist in macrophages, and homozygotes for the mutation were resistant to LPS, but markedly susceptible to infection with mouse cytomegalovirus. Remarkably, Lps2 mutant mice entirely failed to produce type I interferons in response to a viral infection. It would appear that Lps2 is the most proximal component of a signal integration system required for innate immune responses to both viral and bacterial diseases. Positional cloning revealed that the TIR adapter protein Trif/Ticam-1 is structurally altered by the Lps2 mutation. This adapter is responsible for shared effects of responses to viral and bacterial pathogens.
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PMID:Lps2 and signal transduction in sepsis: at the intersection of host responses to bacteria and viruses. 1462 Jan 35

Toll-like receptors (TLR) are an emerging family of receptors that recognize pathogen-associated molecular patterns and promote the activation of leukocytes and intrinsic renal cells. Ligands of the TLR include exogenous microbial components such as LPS (TLR4), lipoproteins and peptidoglycans (TLR1, -2, -6), viral RNA (TLR3), bacterial and viral unmethylated cytosin-guanosin dinucleotide (CpG)-DNA (TLR9), and endogenous molecules including heat-shock proteins and extracellular matrix molecules. Upon stimulation, TLR induce expression of inflammatory cytokines or costimulatory molecules via the MyD88-dependent and MyD88-independent signaling pathways shared with the interleukin-1 receptors. TLR are differentially expressed on leukocyte subsets and non-immune cells and appear to regulate important aspects of innate and adaptive immune responses. Tubular epithelial cells are among the non-immune cells that express TLR1, -2, -3, -4, and -6, suggesting that these TLR might contribute to the activation of immune responses in tubulointerstitial injury (e.g., bacterial pyelonephritis, sepsis, and transplant nephropathy). In addition, TLR9 has been shown to be involved in antigen-induced immune complex glomerulonephritis and lupus nephritis by regulating humoral and cellular immune responses. TLR are evolutionary conserved regulators of innate and adaptive immune responses. It is likely that TLR are involved in many if not all types of renal inflammation. Here the authors provide an overview on the biology of TLR, summarize the present data on their expression in the kidney, and provide an outlook for the potential roles of TLR in kidney disease.
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PMID:Signaling danger: toll-like receptors and their potential roles in kidney disease. 1503 87

Polymorphonuclear neutrophils (PMNs) are essential in initiation and execution of the acute inflammatory response and subsequent resolution of fungal infection. PMNs, however, may act as double-edged swords, as the excessive release of oxidants and proteases may be responsible for injury to organs and fungal sepsis. To identify regulatory mechanisms that may balance PMN-dependent protection and immunopathology in fungal infections, the involvement of different TLR-activation pathways was evaluated on human PMNs exposed to the fungus Aspergillus fumigatus. Recognition of Aspergillus and activation of PMNs occurred through the involvement of distinct members of the TLR family, each likely activating specialized antifungal effector functions. By affecting the balance between fungicidal oxidative and nonoxidative mechanisms, pro- and anti-inflammatory cytokine production, and apoptosis vs necrosis, the different TLRs ultimately impacted on the quality of microbicidal activity and inflammatory pathology. Signaling through TLR2 promoted the fungicidal activity of PMNs through oxidative pathways involving extracellular release of gelatinases and proinflammatory cytokines while TLR4 favored the oxidative pathways through the participation of azurophil, myeloperoxidase-positive, granules and IL-10. This translated in vivo in the occurrence of different patterns of fungal clearance and inflammatory pathology. Both pathways were variably affected by signaling through TLR3, TLR5, TLR6, TLR7, TLR8, and TLR9. The ability of selected individual TLRs to restore antifungal functions in defective PMNs suggests that the coordinated outputs of activation of multiple TLRs may contribute to PMN function in aspergillosis.
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PMID:TLRs govern neutrophil activity in aspergillosis. 1558 66

Toll-like receptors (TLRs) are evolutionary conserved transmembrane proteins that recognize a unique pattern of molecules derived from pathogens or damaged cells, triggering robust but defined innate immune responses. TLR-mediated innate and/or adaptive immune responses play an important role in a variety of diseases including infectious diseases, sepsis, autoimmune diseases, allergy, and atherosclerosis. Each TLR displays a differential expression pattern, intracellular localization and signaling pathway, resulting in distinct immune responses. A variety of new TLR ligands including agonists (e.g. urinary Tamm-Horsfall glycoprotein as a TLR4 ligand, siRNA as TLR3 or 7 ligand, Plasmodium falciparum Hemozoin as a TLR9 ligand, Profilin-like protein in Toxoplasma gondii as a TLR11 ligand) and antagonists (G-rich oligodeoxynucleotides as antagonist for TLR9) have been identified, and some of other TLR ligands are already under clinical trials. The manipulation or intervention of TLR-mediated immune responses is a possible multiple 'Toll' gate for future developments of immunotherapies.
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PMID:'Toll' gates for future immunotherapy. 1710 Jun 16

Streptococcus suis, an important swine and human pathogen, causes septic shock and meningitis. The pathogenesis of both systemic and CNS infections caused by S. suis is poorly understood. A hematogenous model of infection in CD1 mice was developed to study the systemic release of cytokines during the septic shock phase and the proinflammatory events in the CNS associated with this pathogen. Using a liquid array system, high levels of systemic TNF-alpha, IL-6, IL-12, IFN-gamma, CCL2, CXCL1, and CCL5 were observed 24 h after infection and might be responsible for the sudden death of 20% of animals. Infected mice that survived the early sepsis later developed clinical signs of meningitis and exhibited lesions in the meninges and in numerous regions of the brain, such as the cortex, hippocampus, thalamus, hypothalamus, and corpus callosum. Bacterial Ags were found in association with microglia residing only in the affected zones. In situ hybridization combined with immunocytochemistry showed transcriptional activation of TLR2 and TLR3 as well as CD14, NF-kappaB, IL-1beta, CCL2, and TNF-alpha, mainly in myeloid cells located in affected cerebral structures. Early transcriptional activation of TLR2, CD14, and inflammatory cytokines in the choroid plexus and cells lining the brain endothelium suggests that these structures are potential entry sites for the bacteria into the CNS. Our data indicate an important role of the inflammatory response in the pathogenesis of S. suis infection in mice. This experimental model may be useful for studying the mechanisms underlying sepsis and meningitis during bacterial infection.
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PMID:Streptococcus suis serotype 2, an important swine and human pathogen, induces strong systemic and cerebral inflammatory responses in a mouse model of infection. 1764 Oct 51

The bacterium Neisseria meningitidis is the causative agent of meningitis and sepsis. A generally effective vaccine against N. meningitidis serogroup B is not yet available, but outer membrane vesicle vaccines are in development. These vaccines contain lipopolysaccharide (LPS). The inclusion of N. meningitidis wild-type LPS in a vaccine is controversial because of its high toxicity. Therefore, the adjuvant activity of a panel of different Toll-like receptor (TLR) agonists in combination with LPS-deficient meningococcal outer membrane complexes was compared after immunization of mice. The results demonstrate that TLR3, TLR4, TLR7, and TLR9 agonists enhance immune responses against LPS-deficient outer membrane complexes. Their adjuvant activity was characterized by higher levels of antigen-specific immunoglobulin G (IgG), IgG2a, and IgG2b; a higher IgG2a/IgG1 ratio; lower total IgE levels; and most importantly, higher serum bactericidal antibody titers compared to LPS-deficient outer membrane complexes alone.
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PMID:Agonists of Toll-like receptors 3, 4, 7, and 9 are candidates for use as adjuvants in an outer membrane vaccine against Neisseria meningitidis serogroup B. 1790 10

Immune cells express multiple Toll-like receptors (TLRs) that are concomitantly activated by a variety of pathogen products. Although there is presumably a need to coordinate the expression and function of TLRs in individual cells, little is known about the mechanisms governing this process. We show that a protein associated with TLR4 (PRAT4A) is required for multiple TLR responses. PRAT4A resides in the endoplasmic reticulum, and PRAT4A knockdown inhibited trafficking of TLR1 and TLR4 to the cell surface and ligand-induced trafficking of TLR9 to lysosomes. Other cell-surface molecules were expressed normally on immunocytes from PRAT4A-/- mice. There was impaired cytokine production to TLR ligands, except to the TLR3 ligand poly(I:C), and to whole bacteria. Activation of antigen-specific T helper type 1 responses were also defective. Moreover, PRAT4A-/- bone marrow chimeric mice were resistant to lipopolysaccharide-induced sepsis. These results suggest that PRAT4A regulates the subcellular distribution and response of multiple TLRs and is required for both innate and adaptive immune responses.
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PMID:A protein associated with Toll-like receptor (TLR) 4 (PRAT4A) is required for TLR-dependent immune responses. 1799 91

Compound K (C-K), a protopanaxadiol ginsenoside metabolite, was previously shown to have immunomodulatory effects. Here, we describe a novel therapeutic role for C-K in the treatment of lethal sepsis through the modulation of Toll-like receptor (TLR) 4-associated signalling via glucocorticoid receptor (GR) binding. In mononuclear phagocytes, C-K significantly repressed the activation of TLR4/lipopolysaccharide (LPS)-induced NF-kappaB and mitogen-activated protein kinases (MAPKs), as well as the secretion of pro-inflammatory cytokines. However C-K did not affect the TLR3-mediated expression of interferon-beta or the nuclear translocation of IRF-3. C-K competed with the synthetic glucocorticoid dexamethasone for binding to GR and activated glucocorticoid responsive element (GRE)-containing reporter plasmids in a dose-dependent manner. In addition, the blockade of GR with either the GR antagonist RU486 or a siRNA against GR substantially reversed the anti-inflammatory effects of C-K. Furthermore, TLR4-dependent repression of inflammatory response genes by C-K was mediated through the disruption of p65/interferon regulatory factor complexes. Importantly, pre- or post-treatment with C-K significantly rescued mice from Gram-negative bacterial LPS-induced lethal shock by lowering their systemic inflammatory cytokine levels and by reversing the lethal sequelae of sepsis. Collectively, these results demonstrate that C-K, as a functional ligand of GR, regulates distinct TLR4-mediated inflammatory responses, and suggest a novel therapy for Gram-negative septic shock.
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PMID:The ginsenoside metabolite compound K, a novel agonist of glucocorticoid receptor, induces tolerance to endotoxin-induced lethal shock. 1805 81

Endothelial cells (EC) actively participate in the innate defense against microbial pathogens. Under unfavorable conditions, defense reactions can turn life threatening resulting in sepsis. We therefore studied the so far largely unknown EC reaction patterns to the fungal pathogen Candida albicans, which is a major cause of lethality in septic patients. Using oligonucleotide microarray analysis, we identified 56 genes that were transcriptionally up-regulated and 69 genes that were suppressed upon exposure of ECs to C. albicans. The most significantly up-regulated transcripts were found in gene ontology groups comprising the following categories: chemotaxis/migration; cell death and proliferation; signaling; transcriptional regulation; and cell-cell contacts/intercellular signaling. Further examination of candidate signaling cascades established a central role of the proinflammatory NF-kappaB pathway in the regulation of the Candida-modulated transcriptome of ECs. As a second major regulatory pathway we identified the stress-activated p38 MAPK pathway, which critically contributes to the regulation of selected Candida target genes such as CXCL8/IL-8. Depletion of MyD88 and IL-1R-associated kinase-1 by RNA interference demonstrates that Candida-induced NF-kappaB activation is mediated by pattern recognition receptor signaling. Additional experiments suggest that C. albicans-induced CXCL8/IL-8 expression is mediated by TLR3 rather than TLR2 and TLR4, which previously have been implicated with MyD88/IkappaB kinase-2/NF-kappaB activation by this fungus in other systems. Our study provides the first comprehensive analysis of endothelial gene responses to C. albicans and presents novel insights into the complex signaling patterns triggered by this important pathogen.
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PMID:Candida albicans triggers activation of distinct signaling pathways to establish a proinflammatory gene expression program in primary human endothelial cells. 1805 90

Mortality from sepsis has remained high despite recent advances in supportive and targeted therapies. Toll-like receptors (TLRs) sense bacterial products and stimulate pathogenic innate immune responses. Mice deficient in the common adapter protein MyD88, downstream from most TLRs, have reduced mortality and acute kidney injury (AKI) from polymicrobial sepsis. However, the identity of the TLR(s) responsible for the host response to polymicrobial sepsis is unknown. Here, we show that chloroquine, an inhibitor of endocytic TLRs (TLR3, 7, 8, 9), improves sepsis-induced mortality and AKI in a clinically relevant polymicrobial sepsis mouse model, even when administered 6 h after the septic insult. Chloroquine administration attenuated the decline in renal function, splenic apoptosis, serum markers of damage to other organs, and prototypical serum pro- and anti-inflammatory cytokines TNF-alpha and IL-10. An oligodeoxynucleotide inhibitor (H154) of TLR9 and TLR9-deficient mice mirror the actions of chloroquine in all functional parameters that we tested. In addition, chloroquine decreased TLR9 protein abundance in spleen, further suggesting that TLR9 signaling may be a major target for the protective actions of chloroquine. Our findings indicate that chloroquine improves survival by inhibiting multiple pathways leading to polymicrobial sepsis and that chloroquine and TLR9 inhibitors represent viable broad-spectrum and targeted therapeutic strategies, respectively, that are promising candidates for further clinical development.
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PMID:Chloroquine and inhibition of Toll-like receptor 9 protect from sepsis-induced acute kidney injury. 1830 95


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