Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Streptococcus suis is a common cause of sepsis, meningitis, and other serious infections in young piglets and also causes meningitis in humans. The cell-binding specificity of sialic acid-recognizing strains of Streptococcus suis was investigated. Treatment of human erythrocytes with sialidase or mild periodate abolished hemagglutination. Hemagglutination inhibition experiments with sialyl oligosaccharides indicated that the adhesin preferred the sequence NeuNAc alpha 2-3Gal beta 1-4Glc(NAc). Resialylation of desialylated erythrocytes with Gal beta 1-3(4)GlcNAc alpha 2-3-sialyltransferase induced a strong hemagglutination, whereas no or only weak hemagglutination was obtained with cells resialylated with two other sialyltransferases. Binding of radiolabeled bacteria to blots of erythrocyte membrane proteins revealed binding to the poly-N-acetyllactosamine-containing components Band 3, Band 4.5, and polyglycosyl ceramides and to glycophorin A. The involvement of glycophorin A as a major ligand was excluded by the strong hemagglutination of trypsin-treated erythrocytes and En(a-) erythrocytes defective in glycophorin A. Sensitivity of the hemagglutination toward endo-beta-galactosidase treatment of erythrocytes and inhibition by purified poly-N-acetyllactosaminyl glycopeptides indicated that the adhesin bound to glycans containing the following structure: NeuNAc alpha 2-3Gal beta 1-4GlcNAc beta 1-3Gal beta 1-.
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PMID:Identification of N-acetylneuraminyl alpha 2-->3 poly-N-acetyllactosamine glycans as the receptors of sialic acid-binding Streptococcus suis strains. 140 Apr 20

One percent of circulating IgG in humans recognizes galactose alpha 1,3 galactose residues (anti-Gal) and is synthesized in response to stimulation by enteric bacteria. In this study, we found that the prevalence of binding of anti-Gal to blood isolates is significantly higher than its binding to normal stool isolates. When anti-Gal bound onto the lipopolysaccharide of a representative blood isolate, Serratia marcescens #21, it blocked its alternative complement pathway (ACP) lysis and made the organism serum resistant. In contrast, when anti-Gal bound to the capsular polysaccharide of a serum sensitive Serratia, #7, it increased ACP killing of this strain. The mechanism of blockade of ACP lysis by anti-Gal did not involve a decrease in the number of C3 molecules deposited onto Serratia #21 or an inhibition of the binding of C3b to its LPS, nor did it change the iC3b and C3d degradation products of bound C3b or prevent membrane attack complex formation on this organism. Our findings suggest that the effect of anti-Gal on immune lysis is dependent on the bacterial outer membrane structure to which it binds. We postulate that anti-Gal may play a role in the survival of selected Enterobacteriacae in Gram-negative sepsis by blocking ACP-mediated lysis of such bacteria by the nonimmune host, and that this effect depends on where anti-Gal finds its epitope on the bacterial outer membrane.
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PMID:Human natural anti-Gal IgG regulates alternative complement pathway activation on bacterial surfaces. 155 84

Digalactoside-binding (Gal-Gal) pili and alpha-hemolysin of Escherichia coli have been implicated as important virulence determinants in the pathogenesis of human ascending, nonobstructive pyelonephritis. The pathogenic significance of these determinants was evaluated in vitro and in the BALB/c mouse pyelonephritis model by employing wild-type, avirulent laboratory, and genetically defined cosmids, transformants, and recombinant strains. In vitro data suggest that the cytolytic activity of hemolysin is significantly (P less than 0.05) enhanced among digalactoside-binding strains which agglutinate erythrocytes. The basis of increased hemolysis is related presumably to more efficient delivery of the toxin to target lipid substrate in the host plasma membrane. Intravesicular administration of bacteria that express both digalactoside binding and hemolysin generally resulted in greater mortality and renal parenchymal injury in mice than strains that expressed none or only one of these determinants. Analyses convincingly demonstrate that digalactoside-binding pili are correlated with upper urinary tract colonization and that hemolysin is correlated with septicemia and renal parenchymal damage. These determinants collectively constitute the minimal virulence factors to produce disease in this model. Their efficacy as vaccines for the prevention of pyelonephritis was also assessed. A purified Gal-Gal pilus vaccine prevented (P less than 0.05) subsequent colonization by a challenge wild-type strain that exhibited homologous pili. The hemolysin vaccine did not abrogate subsequent bacterial renal colonization on challenge, but it did protect (P less than 0.05) mice which survived challenge from subsequent renal injury compared with those in the saline control group. The combination of these determinants was also protective. The combination of Gal-Gal pili and hemolysin in a vaccine preparation represents a potentially worthwhile strategy for human immunoprophylaxis against pyelonephritis by interdicting several steps in the pathogenesis of a bacterial mucosal infection.
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PMID:Alpha-hemolysin contributes to the pathogenicity of piliated digalactoside-binding Escherichia coli in the kidney: efficacy of an alpha-hemolysin vaccine in preventing renal injury in the BALB/c mouse model of pyelonephritis. 167 76

The erythrocyte receptors for S-fimbriated Escherichia coli, which causes sepsis and meningitis in newborn infants, were investigated. Neuraminidase and trypsin treatments of erythrocytes abolished the hemagglutination ability of the bacteria. To identify the receptor glycoproteins, we separated erythrocyte membrane proteins by gel electrophoresis, blotted them to nitrocellulose, and incubated them with 125I-labeled bacteria. The only bacterium-binding bands identified corresponded to glycophorin A dimer and monomer, and the binding was abolished by neuraminidase treatment of the blot. Radiolabeled bacteria also bound to purified glycophorin A adsorbed to polyvinyl chloride microwells, and the binding was inhibited by other sialoglycoproteins and isolated sialyloligosaccharides containing the NeuAc alpha 2-3Gal sequence. Oligosaccharides which contain the NeuAc alpha 2-3Gal beta 1-3GalNAc and NeuAc alpha 2-3Gal beta 1-3(NeuAc alpha 2-6)GalNAc sequence and which are identical to the O-linked saccharides of glycophorin A were twofold more effective inhibitors of binding than were other oligosaccharides containing the NeuAc alpha 2-3Gal sequence. The replacement of sialic acid in asialoerythrocytes with a purified Gal beta 1-3GalNAc alpha 2-3 sialyltransferase, which forms the O-linked NeuAc alpha 2-3Gal beta 1-3GalNAc sequence in asialoglycophorins, restored bacterial hemagglutination. These results indicated that the major erythrocyte receptor for S-fimbriated E. coli is the NeuAc alpha 2-3Gal beta 1-3GalNAc sequence of the O-linked oligosaccharide chains of glycophorin A.
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PMID:Identification of the O-linked sialyloligosaccharides of glycophorin A as the erythrocyte receptors for S-fimbriated Escherichia coli. 287 51

Streptococcus suis causes meningitis, sepsis, and other serious infections in newborn and young pigs and in adult humans. The Gal alpha 1-4Gal-binding adhesin of S. suis was purified to homogeneity by ultrasonic treatment, fractional ammonium sulfate precipitation, and preparative polyacrylamide gel electrophoresis. Pigeon ovomucoid, a glycoprotein with Gal alpha 1-4Gal terminals, was used to detect the adhesin by blotting. The purified adhesin appeared as single band of an apparent size of 18 kDa and of a pI of 6.4; no disulfide bridges were present. The amount of adhesin as revealed by pigeon ovomucoid binding correlated with the hemagglutination activity of different S. suis strains. The purified adhesin bound to latex particles induced hemagglutination which was specifically inhibited with the same inhibitors as hemagglutination by the intact bacteria, thus demonstrating that the purified protein was the Gal alpha 1-4Gal-recognizing adhesin of S. suis. Two adhesin variants (PN and PO) with differing Gal alpha 1-4Gal binding specificity had the similar electrophoretic mobilities and the same N-terminal peptide sequences, indicating that they were closely related. This represents the first isolation of an adhesin with well-defined cell surface carbohydrate binding activity from Gram-positive bacteria associated with meningitis.
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PMID:Purification of a galactosyl-alpha 1-4-galactose-binding adhesin from the gram-positive meningitis-associated bacterium Streptococcus suis. 749 14

Previous studies with scanning electron microscopy (SEM) have suggested that pigment gallstones contain bacteria. We set out to culture these bacteria and to study their membrane characteristics. We studied gallstones from 54 patients (36 men, 18 women; mean age 55.4 years) admitted consecutively to two hospitals for cholecystectomy. SEM detected bacteria in all of 14 brown pigment stones, 2 of 14 black pigment stones, and in the pigmented centres of 9 of 19 mixed cholesterol stones; no bacteria were detected in 14 pure cholesterol stones or within the cholesterol portions of mixed stones. We were able to culture bacteria from all gallstones with bacteria seen on SEM and for which sufficient material was available (n = 16). 20 bacterial species were recovered from these stones. Gallstones containing bacteria were associated with clinical sepsis and cholangitis. All bacteria obtained from gallstones agglutinated human O P1 erythrocytes, which reflects the presence of P1-specific fimbriae. 5 strains were positive for Forssman-antigen-specific fimbriae. None showed evidence of mannose-specific fimbriae. All of the organisms bound anti-Gal, a ubiquitous naturally occurring IgG specific for alpha-galactosyl residues. The presence of P1 fimbriae and alpha-galactosyl residues and the absence of mannose-specific fimbriae distinguish these organisms from gut flora. We postulate that possession of these unusual properties may enhance the ability of bacteria to colonise the biliary tree and initiate pigment gallstone formation.
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PMID:Differences in outer membrane characteristics between gallstone-associated bacteria and normal bacterial flora. 790 54

Streptococcus suis causes sepsis, meningitis, and other serious infections in piglets, and meningitis in humans. Hemagglutination inhibition experiments with mono- and oligosaccharides and glycoproteins indicated that galactose-binding strains of S. suis recognized the Gal alpha 1-4Gal sequence present in the P1 and Pk blood group antigen structures. In thin-layer chromatography overlay assays the bacteria bound to trihexosylceramide (GbO3) but not to globoside (GbO4) or Forssman glycolipid (GbO5), in contrast to P-fimbriated Escherichia coli, which bound only to the latter two. The S. suis adhesin also differed from that of E. coli in that some of the hydrogen bonds formed with the receptor, as determined with chemically modified receptor analogues, were different. In agreement with the binding specificity, the S. suis bacteria agglutinated best among P blood group erythrocytes those of the P1k and P2k type, and from different animal erythrocytes those from rabbit, which express GbO3 as the predominant glycolipid. Binding to frozen sections of pig pharyngeal tissue was decreased by the free GbO3 oligosaccharide and its protein conjugate, which indicated that the corresponding glycolipid may function as receptor for galactose-binding strains of S. suis in pig pharyngeal epithelium.
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PMID:Characterization of a novel bacterial adhesion specificity of Streptococcus suis recognizing blood group P receptor oligosaccharides. 844 Jul 15

Nineteen papC-positive cytotoxic necrotizing factor 1 (CNF1)-producing Escherichia coli isolates from pigs with septicemia or diarrhea were tested for the presence of pap-, sfa-, and afa-related sequences encoding P/Prs, S/F1C, and Dr/AFA adhesins respectively. Production of adhesins by isolates was tested by mannose-resistant hemagglutination (MRHA), sialidase treatment of erythrocytes and particle agglutination tests. Production of P, S, and F1C fimbriae by isolates was also examined by immunofluorescence. All isolates were pap+ by PCR. Eighteen isolates (95%) were MRHA for ovine and human A erythrocytes and exhibited GalNac-GalNac receptor specificity associated with class III P(Prs) adhesins. Fifteen (79%) of the 19 isolates reacted with antisera specific for one or more different P fimbrial serotypes on immunofluorescence. Three of these isolates also demonstrated Gal-Gal receptor specificity associated with class I or II P fimbrial adhesins. Fifteen (79%) of the isolates were sfa+ by PCR. Seven of these isolates exhibited sialidase-sensitive MRHA of bovine and human O erythrocytes and reacted with serum specific for S fimbriae on immunofluorescence. Seven of the 8 sfa+ isolates which were MRHA-negative for bovine erythrocytes reacted with serum specific for F1C fimbriae on immunofluorescence. All isolates produced type 1 fimbriae as determined by mannose-sensitive agglutination of yeast cells. None of the isolates were afa+ by PCR or colony hybridization. Results suggest that most pap+ porcine CNF1-producing E. coli isolates express P fimbriae bearing class III (Prs) type adhesins. In addition, most of these isolates also produce S or F1C fimbriae.
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PMID:Expression of P, S, and F1C adhesins by cytotoxic necrotizing factor 1-producing Escherichia coli from septicemic and diarrheic pigs. 923 24

Meningococcal endotoxin is the major contributor to the pathogenesis of fulminant sepsis and meningitis of meningococcal disease and is a potent activator of the MyD88-dependent and MyD88-independent pathways via the MD-2/TLR4 receptor. To understand better the biological properties of meningococcal endotoxin that initiates these events, the physicochemical structure of Neisseria meningitidis lipopoly(oligo)saccharide (LOS) of the serogroup B wild-type strain NMB (NeuNAc-Gal beta-GlcNAc-Gal beta-Glc beta-Hep2(GlcNAc,Glc alpha)PEA-Kdo2-lipid A, 1,4'-bisphosphorylated +/- PEA, PEtN) and the genetically-defined mutants (gmhB, Kdo2 -lipid A; kdtA, meningococcal lipid A; gmhB-lpxL1, Kdo2penta-acylated lipid A and NMB-lpx1, penta-acylated meningococcal LOS) were assessed in relation to bioactivity. Confirming previous work, Kdo2lipid A was the minimal structure required for optimal activation of the MD-2/TLR4 pathway of human macrophages. Meningococcal lipid A alone was a very weak agonist in stimulating human macrophages, even at high doses. Penta-acylated LOS structures demonstrated a moderate reduction in TLR4/MyD88-dependent signaling and a dramatic decrease in TLR4-TRIF-dependent signaling. For a better understanding of these results, we have performed an analysis of physicochemical parameters of the LOS structures such as the gel-to-liquid crystalline phase transition of the acyl chains, the inclination angle of the diglucosamine backbone with respect to the membrane surface, and the aggregate structure, and have found a very significant correlation of these parameters with biological activities extending our concept of endotoxicity.
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PMID:Physicochemical characterization and biological activity of lipooligosaccharides and lipid A from Neisseria meningitidis. 1818 62

The pharmacological use of adenosine triphosphate (ATP), although promising, is restricted due to poor cellular penetration and drastic hydrolysis that is markedly accelerated in vivo by ectoenzymes. In the literature, liposomes have proven efficient in offering a physical barrier to extracellular enzymes and favor penetration into cells. First, this review addresses the issues raised by ATP development in pharmaceutics. Second, studies conducted with ATP liposomally entrapped (lipo-ATP) are described, including pharmaco-technical formulation engineering and related models of assessment. Finally, potential directions for research to better target ATP penetration into the liver are considered. Lipo-ATP were formulated for a number of applications, including sepsis-related disorders; spermatozoid alteration; brain ischemia episodes; and ophthalmic, cardiac, and hepatic use. Key formulation parameters need to be carefully considered to optimize stability and entrapment yield value, and to define the manufacturing process. Positive lipids, such as stearylamine, increase entrapment yield value by electrostatic interaction with negatively charged ATP. A freezing-thawing step in the manufacturing process considerably increases entrapment yield value. Lipo-ATP were assessed using cell culture, isolated organs, and animal experimental models. Very promising results were obtained with antimyosin PEGylated immunoliposomes using isolated rat hearts and experimental myocardial infarction in rabbits. In hepatic applications, lipo-ATP are effective in preventing liver injury during shock and to improve the energy status of cold-stored rat liver, in particular, if liposomes are loaded with apolipoprotein E (ApoE). For liver delivery, liposome size needs to be lower than 100 nm to allow diffusion through the Disse space, but liposome flexibility and lipid content may also influence liver uptake. The role of the liposome charge remains unclear. ApoE and the ligand for the asialoglycoprotein receptor [ASGPr) were both used in the literature, but the ASGPr seems more promising. Ligand-ASGPr interaction is based on the sugar preference (N-acetylgalactosamine>>galactose), the antennary structure (tetra>tri>di>monoantennary), and sugar spacing. Numerous high-affinity ligands have been extracted or designed to target hepatocytes, which can be classified according to their origin (i.e., natural, hemisynthetic, or synthetic). Synthetic ASGPr, such as Gal-C4-Chol (cholesten-5-yloxy-N-(4-((1-imino-2-D-thiogalactosylethyl)formamide), are composed of a lipid anchor (e.g., cholesteryl), a spacer (C2 to C6 chain), and a sugar head (galactose or lactose). The formulation includes ligand incorporation, by either simple preincubation or covalent graft, onto preformulated liposomes or direct mixing with other lipids. The ligand-loaded liposomes encapsulated pharmacological agents, markers, or plasmid DNA. Interesting results were obtained with antitumor or antioxidant agents to promote drug penetration in cell culture (e.g., primary rat hepatocyte or HepG2) and specific targeting to hepatocyte in isolated perfused liver (pharmacokinetic studies). Effectiveness was demonstrated in experimental models (e.g., tumor-bearing animals and hepatotoxic models). These targeted formulations were less toxic than standard formulations and controls. A development scheme that can be applied to other drugs, which may benefit from improved hepatic targeting, is proposed to optimize liposome characteristics and ligand structure, including verifications such as the displacement-binding test, ligand incorporation, cell internalization, tissue diffusion, organ and receptor specificity, and efficiency in experimental models.
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PMID:Current data on ATP-containing liposomes and potential prospects to enhance cellular energy status for hepatic applications. 1854 Aug 41


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