Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004623 (bacterial infection)
 15,226 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bacterial diseases, especially those of the lung caused by Gram-negative bacteria, inflict significant economic loss associated with mortality and morbidity in domestic animals. Toll-like receptor 4 (TLR4) has recently been recognized as a major receptor for cellular interactions with lipopolysaccharides derived from Gram-negative bacteria. However, there are no data on the expression of TLR4 in various organs of domestic animals. We performed immunohistochemistry and immuno-gold electron microscopy to localize TLR4 in lung and seven other organs from normal pig, dog and calf (n=2 each) and in inflamed lungs from calves (n=4) challenged with Mannheimia hemolytica. The data show TLR4 in macrophages in lung, small intestine, liver and spleen in all the species and pulmonary intravascular macrophages in calves and pigs. Epithelium in lung, small intestine, cornea and convoluted and straight renal tubules was stained for TLR4. Vascular endothelium of large blood vessels only in lungs and skin was positive, and skeletal muscles were negative for TLR4. In inflamed lungs, airway epithelium showed reduced staining for TLR4 while staining in macrophages remained unaltered. These are the first immunocytochemical data on TLR4 expression in domestic animal species and show similarity in TLR4 staining in macrophages, epithelium and vascular endothelium among dog, pig and cattle.
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PMID:Toll-like receptor 4 in normal and inflamed lungs and other organs of pig, dog and cattle. 1537 63

Toll-like receptor 4 (TLR4) mediates the response to lipopolysaccharide, and its activation induces the expression of a large number of inflammatory genes, many of which are also induced by other pathogen-associated molecular patterns. Interestingly, the subset of genes that are dependent on TLR4 for optimal expression during gram-negative bacterial infection has not been determined. We have previously shown that TLR4-deficient mice rapidly develop acute pneumonia after inoculation with Bordetella bronchiseptica, suggesting that TLR4 is required for expression of early elicited gene products in this model. Microarray analysis with macrophages derived from wild-type and TLR4-deficient mice was used to identify genes whose expression, within 1 h of bacterial exposure, is dependent on TLR4. The results of this investigation suggest that TLR4 is not required for the majority of the transcriptional response to B. bronchiseptica. However, early tumor necrosis factor alpha (TNF-alpha) mRNA expression is primarily dependent on TLR4 and in vitro and in vivo protein levels substantiate this finding. TLR4-deficient mice and TNF-alpha-/- mice are similarly susceptible to infection with relatively low doses of B. bronchiseptica and in vivo neutralization studies indicate that it is the TLR4-dependent early elicited TNF-alpha response that is critical for preventing severe pneumonia and limiting bacterial growth. These results suggest that one critical role for TLR4 is the generation of a robust but transient TNF-alpha response that is critical to innate host defense during acute gram-negative respiratory infection.
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PMID:Toll-like receptor 4-dependent early elicited tumor necrosis factor alpha expression is critical for innate host defense against Bordetella bronchiseptica. 1550 98

Some data suggest that the central nervous system (CNS) is the main target of Staphylococcus alpha-toxin. Since this pathogen cannot penetrate the blood-brain barrier (BBB), the exact mechanism by which alpha-toxin affects the CNS remains unclear. Recent studies on the role of the innate immune system have shed light on how bacterial infections initiate inflammatory responses within the CNS. The aim of this study was to investigate the immunoexpression of Toll-like receptors (TLR 2, TLR 4) in brains of young rats systemically exposed to Staphylococcus alpha-toxin or injured by neonatal hypoxia-ischaemia. The study was carried out on 6-week-old Wistar rats. A group of 6-week-old rats with severe brain injury caused by neonatal hypoxia-ischaemia was also studied separately. In all control rats, the immunoexpression of TLR 2 and TLR 4 was not detected. However, the expression of both TLRs was evident in all brains injured by HI or exposed to alpha-toxin. The immunoexpression was localised in the wall of the small brain vessels, cells of ependyma and leptomeninges. In such vessels the spectrum of ultrastructural lesions was found. The presence of TLR4 detected in the nerve cells of the subcortical gray matter of the brain is particularly of interest, but requires further studies. The presence of TLR 4 antigen in the nerve cells of the subcortical gray matter is particularly of interest. In conclusion, the results show that brain microvessels through TLRs may participate in the immune response of brain affected by bacterial infection as well as injured by non-infection insults.
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PMID:Toll-like receptors in rat brains injured by hypoxic-ischaemia or exposed to staphylococcal alpha-toxin. 1553 30

The chain length of bacterial lipopolysaccharide (LPS) is a crucial factor for host-pathogen interaction during bacterial infection. While rough (R)-type and smooth (S)-type LPSs have been shown to differ in their ability to interact with the bactericidal/permeability-increasing protein, little is known about the differential mode of interaction with the acute-phase reactant LPS-binding protein (LBP). At lower concentrations, LBP catalyzes the binding of LPS to CD14 and enhances LPS-induced cellular activation via Toll-like receptor 4. In humans, however, concentrations of LBP in serum increase during an acute-phase response, and these LBP concentrations exhibit inhibitory effects in terms of cellular activation. The mechanisms of inhibition of LPS effects by LBP are not completely understood. Here, we report that human high-dose LBP (hd-LBP) suppresses binding of both R-type and S-type LPS to CD14 and inhibits LPS-induced nuclear translocation of NF-kappaB, although cellular uptake of R-type LPS was found to be increased by hd-LBP. In contrast, we found that hd-LBP enhanced the binding and uptake of S-type LPS only under serum-free conditions, whereas in the presence of serum, hd-LBP inhibited cellular binding and uptake. This inhibitory effect of serum could be mimicked by the addition of purified high-density lipoprotein (HDL) to serum-free medium, indicating an LBP-mediated transfer of preferentially S-type LPS to plasma lipoproteins such as HDL. A complete understanding of the host's mechanisms to modulate the proinflammatory effects of LPS will most likely help in the understanding of inflammation and infection and may lead to novel therapeutic intervention strategies.
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PMID:Acute-phase concentrations of lipopolysaccharide (LPS)-binding protein inhibit innate immune cell activation by different LPS chemotypes via different mechanisms. 1561 54

Sepsis, a common sequela to Gram-negative pneumonia, results in considerable morbidity and mortality in hospitalized patients. The goal of this study was to determine whether Gram-negative pneumonia alters the expression TLR2, TLR4, and MD2 in lungs or in organs distant to the site of the primary infection. The cDNA sequence coding open reading frames for rabbit TLR2, TLR4, and MD2 were cloned and expressed in Escherichia coli, and specific polyclonal antibodies and polymerase chain reaction (PCR) probes were produced to identify changes in these receptors in rabbits with Gram-negative pneumonia. Using tissues from lungs and distant organs, we show that TLR2, TLR4, and MD2 gene expression is differentially regulated in rabbits with E. coli pneumonia. The increased expression of TLR2 and TLR4 could play an important role in the innate immune response to bacterial infection in the lungs, and improve pathogen recognition and bacterial clearance. In contrast, the increased gene expression of TLR2, TLR4, and MD2 in organs distant to the primary site of infection may contribute to the deleterious systemic inflammatory response observed in patients with sepsis.
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PMID:Gene expression of Toll-like receptor-2, Toll-like receptor-4, and MD2 is differentially regulated in rabbits with Escherichia coli pneumonia. 1565 85

TLRs detect specific molecular features of microorganisms and subsequently engage distinct signaling networks through the differential use of Toll/IL-1R (TIR)-domain-containing adapter proteins. In this study, we investigated the control of apoptosis by the TIR domain-containing adapter proteins MyD88, TIR-domain containing adapter protein (TIRAP), TIR-domain-containing adapter-inducing IFN-beta (TRIF), TRIF-related adapter molecule (TRAM), and sterile alpha motifs and beta-catenin/armadillo repeats (SARM). Upon overexpression, TRIF was the sole TIR-adapter to potently engage mammalian cell death signaling pathways. TRIF-induced cell death required caspase activity initiated by the Fas/Apo-1-associated DD protein-caspase-8 axis and was unaffected by inhibitors of the intrinsic apoptotic machinery. The proapoptotic potential of TRIF mapped to the C-terminal region that was found to harbor a receptor interacting protein (RIP) homotypic interaction motif (RHIM). TRIF physically interacted with the RHIM-containing proteins RIP1 and RIP3, and deletion and mutational analyses revealed that the RHIM in TRIF was essential for TRIF-induced apoptosis and contributed to TRIF-induced NF-kappa B activation. The domain that was required for induction of apoptosis could activate NF-kappa B but not IFN regulatory factor-3, yet the activation of NF-kappa B could be blocked by superrepressor I kappa B alpha without blocking apoptosis. Thus, the ability of TRIF to induce apoptosis was not dependent on its ability to activate either IFN regulatory factor-3 or NF-kappa B but was dependent on the presence of an intact RHIM. TRIF serves as an adaptor for both TLR3 and TLR4, receptors that are activated by dsRNA and LPS, respectively. These molecular motifs are encountered during viral and bacterial infection, and the apoptosis that occurs when TRIF is engaged represents an important host defense to limit the spread of infection.
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PMID:Apoptosis induced by the toll-like receptor adaptor TRIF is dependent on its receptor interacting protein homotypic interaction motif. 1581 22

Animals that cannot sense endotoxin may die if they are infected by Gram-negative bacteria. Animals that sense endotoxin and respond too vigorously may also die, victims of their own inflammatory reactions. The outcome of Gram-negative bacterial infection is thus determined not only by an individual's ability to sense endotoxin and respond to its presence, but also by numerous phenomena that inactivate endotoxin and/or prevent harmful reactions to it. Endotoxin sensing requires the MD-2/TLR4 recognition complex and occurs principally in local tissues and the liver. This review highlights the known detoxification mechanisms, which include: (i) proteins that facilitate LPS sequestration by plasma lipoproteins, prevent interactions between the bioactive lipid A moiety and MD-2/TLR4, or promote cellular uptake via non-signaling pathway(s); (ii) enzymes that deacylate or dephosphorylate lipid A; (iii) mechanisms that remove LPS and Gram-negative bacteria from the bloodstream; and (iv) neuroendocrine adaptations that modulate LPS-induced mediator production or neutralize pro-inflammatory molecules in the circulation. In general, the mechanisms for sensing and detoxifying endotoxin seem to be compartmentalized (local versus systemic), dynamic, and variable between individuals. They may have evolved to confine infection and inflammation to extravascular sites of infection while preventing harmful systemic reactions. Integration of endotoxin sensing and detoxification is essential for successful host defense.
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PMID:Detoxifying endotoxin: time, place and person. 1594 33

Infectious complications represent a substantial cause of morbidity and mortality in children undergoing therapy for acute myeloid leukemia (AML). Since it has been shown that alterations in innate immune pathways contribute to the risk for serious infections, we analyzed well-characterized variants in innate immune genes (TNF, IL6, IL8, MPO, CHIT, FCGR2A, TLR2, and TLR4) to determine their possible contribution to infectious complications during therapy for pediatric AML. The study population consisted of 168 North European Caucasian children enrolled on the clinical trial AML-BFM 93. We found an association between Gram-negative bacterial infection and common, functional variants in two genes, IL6 and CHIT. The risk for infection was significantly higher in children with the G allele in the IL6 promoter at -174 bp (P=0.026) and in patients with the H allele of CHIT (P=0.033). The promoter variant in IL6 has been shown to increase expression while the H allele disrupts both function and circulating levels. Our data suggest that variant alleles of both IL6 and CHIT could influence susceptibility to infection with Gram-negative bacteria in children undergoing therapy for AML. Follow-up studies, namely replication association studies and in vitro investigation of these common polymorphisms, are warranted to confirm these observations.
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PMID:Common genetic variants in the interleukin-6 and chitotriosidase genes are associated with the risk for serious infection in children undergoing therapy for acute myeloid leukemia. 1610 86

Prostaglandins have a central role in many endocrine functions in mammals, including regulation of the life span of the corpus luteum by prostaglandin F(2alpha) (PGF) and prostaglandin E2 (PGE), which are secreted by the uterine endometrium. However, the uterus is readily infected with bacteria such as Escherichia coli, which disrupt luteolysis. Immune cells detect E. coli by Toll-like receptor 4 (TLR4) binding its pathogenic ligand, lipopolysaccharide (LPS), although signaling requires accessory molecules such as CD14. The objective of this study was to determine the effect of E. coli or LPS on the function of bovine endometrial cells, and whether purified populations of epithelial and stromal cells express the molecules involved in LPS recognition. In addition, because the female sex hormones estradiol and progesterone modify the risk of uterine infection, their effect on the LPS response was investigated. Endometrial explants produced prostaglandins in response to LPS, with an increased ratio of PGE to PGF. Addition of LPS or E. coli to stromal and epithelial cells stimulated production of PGE and PGF and increased their cyclooxygenase 2 mRNA expression. The production of prostaglandins was abrogated by an LPS antagonist. In addition, estradiol and progesterone inhibited the production of PGE and PGF in response to LPS, indicating a role for steroid hormones in the response to bacterial infection. For the first time, Toll-like receptor 4 mRNA and CD14 mRNA and protein were detected in bovine endometrial stromal and epithelial cells by RT-PCR and flow cytometry. In conclusion, epithelial and stromal cells detect and respond to bacteria, which modulate their endocrine function.
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PMID:Expression and function of Toll-like receptor 4 in the endometrial cells of the uterus. 1622 58

Bacterial infection promotes the infiltration of inflammatory leukocytes mediated in part by receptors for formyl-methionine-terminated peptides. In this study, we show that LPS can markedly enhance the expression of the formyl peptide receptor gene (FPR1) in mouse macrophages and neutrophils by enhancing transcription and by stabilization of the mRNA. In untreated cells, FPR1 mRNA exhibits a half-life of approximately 90 min and this is markedly increased (to >6 h) following stimulation with LPS. Although FPR1 mRNA levels remained elevated over baseline for >20 h after stimulation, the half-life of the message is prolonged only transiently. LPS-induced FPR1 mRNA expression is mediated in part by the intermediate production of secreted factors. First, the response to LPS is partially blocked by the translational inhibitor cycloheximide. Second, a heat-labile but polymyxin B-insensitive factor present in supernatants from LPS-treated cells stimulates enhanced expression of FPR1 mRNA and, like LPS, promotes stabilization of FPR1 mRNA. Furthermore, supernatants from LPS-treated wild-type macrophages can stimulate FPR1 mRNA expression in LPS-insensitive macrophages from TLR4-mutant mice. Elevated FPR1 mRNA expression is also induced in response to ligands for TLR2 and TLR3. TNF-alpha but not IL-1, IL-6, IFN-beta, and IFN-gamma can mimic the effects of LPS although other factors apparently also contribute. Collectively, these findings define a distinct molecular pattern of response to TLR stimulation in inflammatory phagocytes and demonstrate that regulation of FPR1 expression is achieved through both transcriptional and posttranscriptional mechanisms.
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PMID:Lipopolysaccharide induces formyl peptide receptor 1 gene expression in macrophages and neutrophils via transcriptional and posttranscriptional mechanisms. 1623 4


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