Academic literature on the topic 'Streptococcus pneumoniae toxins'
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Journal articles on the topic "Streptococcus pneumoniae toxins"
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Cornejo, Omar E., Daniel E. Rozen, Robert M. May, and Bruce R. Levin. "Oscillations in continuous culture populations of Streptococcus pneumoniae : population dynamics and the evolution of clonal suicide." Proceedings of the Royal Society B: Biological Sciences 276, no. 1659 (December 3, 2008): 999–1008. http://dx.doi.org/10.1098/rspb.2008.1415.
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Agents that kill or induce suicide in the organisms that produce them or other individuals of the same genotype are intriguing puzzles for ecologists and evolutionary biologists. When those organisms are pathogenic bacteria, these suicidal toxins have the added appeal as candidates for the development of narrow spectrum antibiotics to kill the pathogens that produce them. We show that when clinical as well as laboratory strains of Streptococcus pneumoniae are maintained in continuous culture (chemostats), their densities oscillate by as much as five orders of magnitude with an apparently constant period. This dynamic, which is unanticipated for single clones of bacteria in chemostats, can be attributed to population-wide die-offs and recoveries. Using a combination of mathematical models and experiments with S. pneumoniae , we present evidence that these die-offs can be attributed to the autocatalytic production of a toxin that lyses or induces autolysis in members of the clone that produces it. This toxin, which our evidence indicates is a protein, appears to be novel; S. pneumoniae genetic constructs knocked out for lytA and other genes coding for known candidates for this agent oscillate in chemostat culture. Since this toxin lyses different strains of S. pneumoniae as well as other closely related species of Streptococcus , we propose that its ecological role is as an allelopathic agent. Using a mathematical model, we explore the conditions under which toxins that kill members of the same clone that produces them can prevent established populations from invasion by different strains of the same or other species. We postulate that the production of the toxin observed here as well as other bacteria-produced toxins that kill members of the same genotype, ‘clonal suicide’, evolved and are maintained to prevent colonization of established populations by different strains of the same and closely related species.
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Xu, Yan, Yanbo Wang, Yinan Guo, Lina Wei, Lizhong Ding, Zhongtian Wang, and Liping Sun. "Cortex Cercis chinensis Granules Attenuate Streptococcus pneumoniae Virulence by Targeting Pneumolysin." Evidence-Based Complementary and Alternative Medicine 2020 (June 16, 2020): 1–7. http://dx.doi.org/10.1155/2020/8537026.
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Pore-forming toxins produced by bacteria are some of the most important molecular weapons for bacterial virulence. Pneumolysin (PLY) is a pore-forming toxin secreted by Streptococcus pneumoniae (S. pneumoniae) and plays a vital role in the spread, colonization, and invasion of this bacterium in the host, indicating that PLY is a promising target for developing treatments against S. pneumoniae infection. In this study, Cortex Cercis chinensis granules (CCCGs), a prescription drug on the market, were shown to inhibit the pore-forming activity of PLY and protect against PLY-mediated cell hemolysis and A549 cell death without antibacterial activity or inhibition of PLY production. In addition, CCCG treatment inhibited the oligomerization of PLY. Animal experiments showed that CCCGs can reduce the death of mice infected with S. pneumoniae, the degree of pathological damage to the lungs, and the levels of TNF-α and IL-6 in the lungs. In summary, our results demonstrated that CCCGs, a marketed Chinese medicine, inhibit PLY activity and subsequently attenuate S. pneumoniae virulence, which would offer a novel strategy for fighting S. pneumoniae infection and a new use for CCCGs.
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Price, Katherine E., and Andrew Camilli. "Pneumolysin Localizes to the Cell Wall of Streptococcus pneumoniae." Journal of Bacteriology 191, no. 7 (January 23, 2009): 2163–68. http://dx.doi.org/10.1128/jb.01489-08.
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ABSTRACT Streptococcus pneumoniae is the causative agent of multiple diseases, including otitis media, pneumonia, bacteremia, and meningitis. Pneumolysin (Ply), a member of the cholesterol-dependent cytolytic pore-forming toxins, is produced by virtually all clinical isolates of S. pneumoniae, and strains in which the Ply gene has been deleted are severely attenuated in mouse models of infection. In contrast to all other members of the cholesterol-dependent cytolysin family, Ply lacks a signal peptide for export. Instead, Ply has been hypothesized to be released upon autolysis or, alternatively, via a nonautolytic mechanism that remains ill defined. We determined by use of cell fractionation and Western blotting that, during in vitro growth, exported Ply is localized primarily to the cell wall compartment in 18 different serotypes in the absence of detectable cell lysis. Hemolytic assays revealed that this cell wall-localized Ply is active. Additionally, cell wall-localized Ply is accessible to extracellular protease and is detergent releasable.
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Ahn, Danielle, and Alice Prince. "Participation of Necroptosis in the Host Response to Acute Bacterial Pneumonia." Journal of Innate Immunity 9, no. 3 (2017): 262–70. http://dx.doi.org/10.1159/000455100.
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Common pulmonary pathogens, such as Streptococcus pneumoniae and Staphylococcus aureus, as well as the host-adapted pathogens responsible for health care-associated pneumonias, such as the carbapenem-resistant Klebsiella pneumoniae and Serratia marcecsens, are able to activate cell death through the RIPK1/RIPK3/MLKL cascade that causes necroptosis. Necroptosis can influence the pathogenesis of pneumonia through several mechanisms. Activation of this pathway can result in the loss of specific types of immune cells, especially macrophages, and, in so doing, contribute to host pathology through the loss of their critical immunoregulatory functions. However, in other settings of infection, necroptosis promotes pathogen removal and the eradication of infected cells to control excessive proinflammatory signaling. Bacterial production of pore-forming toxins provides a common mechanism to activate necroptosis by diverse bacterial species, with variable consequences depending upon the specific pathogen. Included in this brief review are data demonstrating the ability of the carbapenem-resistant ST258 K. pneumoniae to activate necroptosis in the setting of pneumonia, which is counterbalanced by their suppression of CYLD expression. Exactly how necroptosis and other mechanisms of cell death are coregulated in the response to specific pulmonary pathogens remains a topic of active investigation, and it may provide potential therapeutic targets in the future.
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Yau, Belinda, Nicholas Hunt, Andrew Mitchell, and Lay Too. "Blood‒Brain Barrier Pathology and CNS Outcomes in Streptococcus pneumoniae Meningitis." International Journal of Molecular Sciences 19, no. 11 (November 11, 2018): 3555. http://dx.doi.org/10.3390/ijms19113555.
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Streptococcus pneumoniae is a major meningitis-causing pathogen globally, bringing about significant morbidity and mortality, as well as long-term neurological sequelae in almost half of the survivors. Subsequent to nasopharyngeal colonisation and systemic invasion, translocation across the blood‒brain barrier (BBB) by S. pneumoniae is a crucial early step in the pathogenesis of meningitis. The BBB, which normally protects the central nervous system (CNS) from deleterious molecules within the circulation, becomes dysfunctional in S. pneumoniae invasion due to the effects of pneumococcal toxins and a heightened host inflammatory environment of cytokines, chemokines and reactive oxygen species intracranially. The bacteria‒host interplay within the CNS likely determines not only the degree of BBB pathological changes, but also host survival and the extent of neurological damage. This review explores the relationship between S. pneumoniae bacteria and the host inflammatory response, with an emphasis on the BBB and its roles in CNS protection, as well as both the acute and long-term pathogenesis of meningitis.
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Martner, Anna, Claes Dahlgren, James C. Paton, and Agnes E. Wold. "Pneumolysin Released during Streptococcus pneumoniae Autolysis Is a Potent Activator of Intracellular Oxygen Radical Production in Neutrophils." Infection and Immunity 76, no. 9 (June 16, 2008): 4079–87. http://dx.doi.org/10.1128/iai.01747-07.
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ABSTRACT Streptococcus pneumoniae is a major cause of otitis media, pneumonia, meningitis, and septicemia in humans. The host defense against this pathogen largely depends on bacterial killing by neutrophils. A peculiar property of pneumococci is their tendency to undergo autolysis, i.e., autoinduced disruption of the bacterial cell wall mediated by activation of the enzyme LytA, under stationary growth conditions. LytA is a virulence factor, but the molecular background for this has not been fully clarified. Here we examine how bacterial compounds released upon autolysis affect the production of reactive oxygen species (ROS) in neutrophils. We found that the S. pneumoniae strains A17 and D39 induced activation of the NADPH oxidase and the production of ROS in human neutrophils and that this activation was blocked when LytA was inactivated. The ROS-inducing bacterial substance released from autolyzed bacteria was identified as the cytoplasmic toxin pneumolysin. Further screening of clinical pneumococcal strains of various sero- and genotypes revealed that selected strains expressing toxins with reduced pneumolysin-dependent hemolytic activity had decreased abilities to induce ROS in neutrophils. Furthermore, a mutated form of purified pneumolysin lacking hemolytic and complement binding functions (PdT) did not induce any oxygen radical production. The ROS produced in response to pneumolysin formed mainly intracellularly, which may explain why this production was not detected previously. ROS released intracellularly may function as signaling molecules, modifying the function of neutrophils in bacterial defense.
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Nieto, Concha, Izhack Cherny, Seok Kooi Khoo, Mario García de Lacoba, Wai Ting Chan, Chew Chieng Yeo, Ehud Gazit, and Manuel Espinosa. "The yefM-yoeB Toxin-Antitoxin Systems of Escherichia coli and Streptococcus pneumoniae: Functional and Structural Correlation." Journal of Bacteriology 189, no. 4 (October 27, 2006): 1266–78. http://dx.doi.org/10.1128/jb.01130-06.
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ABSTRACT Toxin-antitoxin loci belonging to the yefM-yoeB family are located in the chromosome or in some plasmids of several bacteria. We cloned the yefM-yoeB locus of Streptococcus pneumoniae, and these genes encode bona fide antitoxin (YefM Spn ) and toxin (YoeB Spn ) products. We showed that overproduction of YoeB Spn is toxic to Escherichia coli cells, leading to severe inhibition of cell growth and to a reduction in cell viability; this toxicity was more pronounced in an E. coli B strain than in two E. coli K-12 strains. The YoeB Spn -mediated toxicity could be reversed by the cognate antitoxin, YefM Spn , but not by overproduction of the E. coli YefM antitoxin. The pneumococcal proteins were purified and were shown to interact with each other both in vitro and in vivo. Far-UV circular dichroism analyses indicated that the pneumococcal antitoxin was partially, but not totally, unfolded and was different than its E. coli counterpart. Molecular modeling showed that the toxins belonging to the family were homologous, whereas the antitoxins appeared to be specifically designed for each bacterial locus; thus, the toxin-antitoxin interactions were adapted to the different bacterial environmental conditions. Both structural features, folding and the molecular modeled structure, could explain the lack of cross-complementation between the pneumococcal and E. coli antitoxins.
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Escajadillo, Tamara, and Victor Nizet. "Pharmacological Targeting of Pore-Forming Toxins as Adjunctive Therapy for Invasive Bacterial Infection." Toxins 10, no. 12 (December 17, 2018): 542. http://dx.doi.org/10.3390/toxins10120542.
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For many of the most important human bacterial infections, invasive disease severity is fueled by the cell damaging and pro-inflammatory effects of secreted pore-forming toxins (PFTs). Isogenic PFT-knockout mutants, e.g., Staphylococcus aureus lacking α-toxin or Streptococcus pneumoniae deficient in pneumolysin, show attenuation in animal infection models. This knowledge has inspired multi-model investigations of strategies to neutralize PFTs or counteract their toxicity as a novel pharmacological approach to ameliorate disease pathogenesis in clinical disease. Promising examples of small molecule, antibody or nanotherapeutic drug candidates that directly bind and neutralize PFTs, block their oligomerization or membrane receptor interactions, plug establishment membrane pores, or boost host cell resiliency to withstand PFT action have emerged. The present review highlights these new concepts, with a special focus on β-PFTs produced by leading invasive human Gram-positive bacterial pathogens. Such anti-virulence therapies could be applied as an adjunctive therapy to antibiotic-sensitive and -resistant strains alike, and further could be free of deleterious effects that deplete the normal microflora.
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Hirst, Robert A., Kulvinder S. Sikand, Andrew Rutman, Timothy J. Mitchell, Peter W. Andrew, and Christopher O'Callaghan. "Relative Roles of Pneumolysin and Hydrogen Peroxide from Streptococcus pneumoniae in Inhibition of Ependymal Ciliary Beat Frequency." Infection and Immunity 68, no. 3 (March 1, 2000): 1557–62. http://dx.doi.org/10.1128/iai.68.3.1557-1562.2000.
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ABSTRACT Ciliated ependymal cells line the ventricular system of the brain and the cerebral aqueducts. This study characterizes the relative roles of pneumolysin and hydrogen peroxide (H2O2) in pneumococcal meningitis, using the in vitro ependymal ciliary beat frequency (CBF) as an indicator of toxicity. We have developed an ex vivo model to examine the ependymal surface of the brain slices cut from the fourth ventricle. The ependymal cells had cilia beating at a frequency of between 38 and 44Hz. D39 (wild-type) and PLN-A (pneumolysin-negative) pneumococci at 108 CFU/ml both caused ciliary slowing. Catalase protected against PLN-A-induced ciliary slowing but afforded little protection from D39. Lysed PLN-A did not reduce CBF, whereas lysed D39 caused rapid ciliary stasis. There was no effect of catalase, penicillin, or catalase plus penicillin on the CBF. H2O2 at a concentration as low as 100 μM caused ciliary stasis, and this effect was abolished by coincubation with catalase. An additive inhibition of CBF was demonstrated using a combination of both toxins. A significant inhibition of CBF at between 30 and 120 min was demonstrated with both toxins compared with either H2O2 (10 μM) or pneumolysin (1 HU/ml) alone. D39 released equivalent levels of H2O2 to those released by PLN-A, and these concentrations were sufficient to cause ciliary stasis. The brain slices did not produce H2O2, and in the presence of 108 CFU of D39 or PLN-A per ml there was no detectable bacterially induced increase of H2O2release from the brain slice. Coincubation with catalase converted the H2O2 produced by the pneumococci to H2O. Penicillin-induced lysis of bacteria dramatically reduced H2O2 production. The hemolytic activity released from D39 was sufficient to cause rapid ciliary stasis, and there was no detectable release of hemolytic activity from the pneumolysin-negative PLN-A. These data demonstrate that D39 bacteria released pneumolysin, which caused rapid ciliary stasis. D39 also released H2O2, which contributed to the toxicity, but this was masked by the more severe effects of pneumolysin. H2O2 released from intact PLN-A was sufficient to cause rapid ciliary stasis, and catalase protected against H2O2-induced cell toxicity, indicating a role for H2O2 in the response. There is also a slight additive effect of pneumolysin and H2O2 on ependymal toxicity; however, the precise mechanism of action and the role of these toxins in pathogenesis remain unclear.
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Braun, Johann S., Olaf Hoffmann, Miriam Schickhaus, Dorette Freyer, Emilie Dagand, Daniela Bermpohl, Tim J. Mitchell, Ingo Bechmann, and Joerg R. Weber. "Pneumolysin Causes Neuronal Cell Death through Mitochondrial Damage." Infection and Immunity 75, no. 9 (June 11, 2007): 4245–54. http://dx.doi.org/10.1128/iai.00031-07.
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ABSTRACT Bacterial toxins such as pneumolysin are key mediators of cytotoxicity in infections. Pneumolysin is a pore-forming toxin released by Streptococcus pneumoniae, the major cause of bacterial meningitis. We found that pneumolysin is the pneumococcal factor that accounts for the cell death pathways induced by live bacteria in primary neurons. The pore-forming activity of pneumolysin is essential for the induction of mitochondrial damage and apoptosis. Pneumolysin colocalized with mitochondrial membranes, altered the mitochondrial membrane potential, and caused the release of apoptosis-inducing factor and cell death. Pneumolysin induced neuronal apoptosis without activating caspase-1, -3, or -8. Wild-type pneumococci also induced apoptosis without activation of caspase-3, whereas pneumolysin-negative pneumococci activated caspase-3 through the release of bacterial hydrogen peroxide. Pneumolysin caused upregulation of X-chromosome-linked inhibitor of apoptosis protein and inhibited staurosporine-induced caspase activation, suggesting the presence of actively suppressive mechanisms on caspases. In conclusion, our results indicate additional functions of pneumolysin as a mitochondrial toxin and as a determinant of caspase-independent apoptosis. Considering this, blocking of pneumolysin may be a promising cytoprotective strategy in pneumococcal meningitis and other infections.
Dissertations / Theses on the topic "Streptococcus pneumoniae toxins"
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Walker, John Arthur. "Studies of pneumolysin, the membrane damaging toxin of Streptococcus pneumoniae." Thesis, University of Leicester, 1988. http://hdl.handle.net/2381/35425.
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A recombinant phage that produced a polypeptide possessing the characteristics of pneumolysin, the membrane damaging toxin of the pneumococcus, was isolated from a bank of pneumococcal sequences in ?gt10. Subclones carrying the pneumolysin gene in various plasmids were haemolytic regardless of the orientation of the insert. The nucleotide sequence of a 5 kb fragment carrying the pneumolysin gene was determined. An open reading frame 1413 bp long was identified that when translated encoded a polypeptide with 471 amino acids and a molecular weight 52.8 kD. The N-terminal amino acid sequence of the predicted protein was identical to that of native pneumolysin. A single cysteine residue was present at position 428 in the amino acid sequence. Comparison of the DNA and amino acid sequences of pneumolysin with streptolysin O (SLO) revealed extensive homology in the amino acid sequence. The longest region of identity was a sequence of 12 amino acids surrounding the unique cysteine. A hybrid gene consisting of the 5' region of the pneumolysin gene and the 3' end of the SLO gene was constructed. The fusion polypeptide was made in E. coli, but possessed a very low haemolytic activity. Using the technique of oligonucleotide-mediated site-directed mutagenesis, two mutant genes were constructed in which the cysteine codon was changed to either a glycine or serine codon. Modified toxins when purified from E. coli had a specific activity of about 1-2 % that of wild type pneumolysin.
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Saunders, Frances Katharine. "Studies on pneumolysin, the thiol-activated toxin of Streptococcus pneumoniae." Thesis, University of Leicester, 1992. http://hdl.handle.net/2381/35416.
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In addition to being haemolytic, pneumolysin, the thiol- activated toxin of Streptococcus pneumoniae, modulates a number of cellular functions at sublytic concentration. The effect of sublytic concentrations of pneumolysin on neutrophil respiratory burst and degranulation was studied, as was the effect of the toxin on the viability of neutrophils at higher toxin concentrations, and pneumolysin -neutrophil binding at both 4 and 37°C. It was demonstrated that neither inhibition of the respiratory burst, nor degranulation, was due to the cytolytic activity of pneumolysin. The use of the modified pneumolysins Cys428 > Ala, Cys428 > Ser, and Cys428 > Gly in these assays revealed that the activity of pneumolysin at cytotoxic concentrations correlated with its haemolytic activity. It was proposed was that the cytotoxic activity of the toxin was due the formation of small pores in the plasma membrane which allowed an influx of calcium into the cell. Parallels were drawn with the subcytocidal effects of other bacterial toxins. Despite inhibiting the respiratory burst of neutrophils, pneumolysin was not found to inhibit their bactericidal activity towards pneumococci. In a murine model of pneumococcal pneumonia, immunisation with pneumolysin was found to extend survival and slow the increase in pneumococcal numbers in the lungs, liver, spleen, brain and blood. Incubation of monocytes with pneumolysin triggered the release of interleukin-1 but not tumour necrosis factor. The role of pneumolysin in the pathogenesis of pneumococcal disease was discussed. Of the 2 regions of homology between pneumolysin and the acute phase protein C-reactive protein, one is known to be important for complement activation by the toxin. Site-directed mutagenesis of the pneumolysin gene showed that the other region of homology was not important for complement activation or haemolysis.
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Owen, Richard H. G. "Structure and function of pneumolysin, the thiol-activated toxin of Streptococcus pneumoniae." Thesis, University of Leicester, 1993. http://hdl.handle.net/2381/35406.
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Streptococcus pneumoniae, or the pneumococcus, is an important pathogen of man. Pneumolysin is a cytolytic toxin produced by the pneumococcus, that binds to all eukaryotic cells tested. The aim of this research project was to locate the cell- binding region of pneumolysin. Two separate strategies were used to locate the cell- binding region of pneumolysin. One approach was to produce a gene library which contained single, random, point mutations throughout the pneumolysin gene. The products of the experiment were screened for mutants which showed reduced haemolytic activity as it was thought that mutants with reduced cell-binding activity would also possess reduced haemolytic activity. The mutants which were found to possess reduced haemolytic activity were to be tested for cell-binding activity. The experiment was performed but no phage were produced. However, by using the same approach, a colleague subsequently produced mutated phage which possessed reduced haemolytic activity. None of these have yet been assayed for cell-binding activity. The other approach was to produce truncated versions of the pneumolysin protein and assay their cell-binding activity. Using this approach it was found that deletion of 20 residues from the C-terminus of pneumolysin completely abolished cell- binding activity. Molecules with smaller C-terminal deletions had much lower cell-binding activity than the intact molecule. Deletion of six residues from the C-terminus of pneumolysin reduced cell-binding activity by 98%. Using site-directed mutagenesis, a proline residue in the C-terminal region of pneumolysin was replaced with serine. The resultant full-length molecule showed a reduction in cell- binding activity of 90% when compared to the wildtype molecule. The results showed that residues in the C-terminal region of pneumolysin are necessary for cell-binding activity.
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Gilbert, Robert John Crispin. "The structure, conformation and mechanism of the bacterial toxin pneumolysin from Streptococcus pneumoniae." Thesis, University of Leicester, 1998. http://hdl.handle.net/2381/9720.
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Pneumolysin is a virulence factor produced by the human pathogen Streptococcus pneumoniae. It acts in disease to damage cell membranes via pore formation and to activate the complement system directly. Pore formation is accompanied by the transition of the protein from an aqueous, monomeric conformation to a lipid-inserted, ring-shaped oligomeric state. This thesis describes the behaviour of pneumolysin in solution, investigations concerning its mechanism of pore formation, and the structure of an oligomeric form of the toxin. Pneumolysin self-interacts in solution through one of its four domains. The self-interaction leads to the formation of dimeric toxin. Consequent upon dimerization, pneumolysin oligomerizes in solution into structures apparently the same as those associated with pore formation in membranes. In addition it forms helical oligomers. Small-angle neutron scattering (SANS) suggests the existence of inter-domain flexibility in pneumolysin. The kinetics of pore formation by pneumolysin are dependent on binding and oligomerization of the toxin. SANS allows the observation of a model membrane under attack by pneumolysin, indicating changes in bilayer structure. The structure of a helical pneumolysin oligomer is described determined by electron cryomicroscopy. This thesis demonstrates that oligomerization is an innate property of pneumolysin, although it was previously thought that the monomer-oligomer transition required interaction between toxin and cholesterol. It furthermore describes a novel approach to observing the interaction between a protein and a membrane in seeking to understand the biochemistry of this important and widespread process. The determination of an oligomeric structure for pneumolysin indicates the orientation of the toxin subunit in the pore for the first time, which is very different from that previously proposed. It is also possible to understand on the basis of the oligomeric structure the relationship between self-association and pore formation by pneumolysin and related toxins.
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El-Rachkidy, Rana Georges. "Relationship of structure to function in the pore-forming toxin pneumolysin from Streptococcus pneumoniae." Thesis, University of Leicester, 2003. http://hdl.handle.net/2381/29840.
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Pneumolysin is an important virulence factor produced by the human pathogen Streptococcus pneumoniae. It belongs to the family of cholesterol dependent cytolysins (CDCs) that damage the target cell membrane, by forming large oligomeric pores of 30 to 80 toxin monomers, where each monomer is thought to contribute at least two p-hairpins. A panel of mutations was done in the two putative transmembrane region of pneumolysin TMH1 and TMH2 located in domain 3 of the toxin monomer, and believed to be lining the pore lumen. The generated mutants exhibited different levels of haemolytic activity, particularly the single mutation W278F, W278D, and the triple mutation (D257N-E258Q-E260Q), largely impaired the haemolytic activity of the wild-type toxin. These mutant toxins along with a previously made lytic deficient mutant W433F were subjected to further studies. Circular dichroism analysis done with those mutants showed that the secondary structure of the native toxin was conserved. The kinetics of release of calcein from liposomes along with the kinetics of lysis of erythrocytes exposed to these mutants was substantially slower than that of the wild-type toxin. Pneumolysin and other CDCs induced pores were studied on model systems like lipid bilayer and liposomes. In this thesis, I demonstrated the formation of pores by pneumolysin on the membrane of a 'real' cell by using the patch-clamp technique. Pneumolysin induced heterogeneous pore on either side of the membrane, of different conductance states, classified as small, medium and large. A stepwise increase in current was observed with early appearance of small conductance channels followed by larger ones. The mutant toxins generated in this work and W433F were also tested with patch clamping. They formed pores of various conductance states with a decrease in the occurrence of large channels, in comparison to the wild-type.
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Faraj, Bayan Hama Amin. "Characterization of the interactions of the Streptococcus pneumoniae toxin, pneumolysin, with soluble molecules of the immune system." Thesis, University of Leicester, 2017. http://hdl.handle.net/2381/40641.
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Pneumolysin (Ply) is a key virulence factor of the bacterium Streptococcus pneumoniae (Pneumococcus). Major functions include forming pores in mammalian cell membranes and activating the complement cascade to divert the host’s immune system. The aim of this thesis was to investigate these processes at the molecular level to understand how Ply facilitates disease by the pneumococcus. Previous studies have suggested that Ply interacts with various soluble molecules of the immune system, including L-ficolin and IgG. These interactions activate complement via the lectin and classical pathways, respectively. In this thesis I have demonstrated that Ply does not interact with either native serum L-ficolin or recombinant human L-ficolin produced in Chinese hamster ovary cells. The previous erroneous report probably arose as a result of contamination of Ply preparations with L-ficolin ligands. Investigation of binding between Ply and IgG showed that Ply binds to IgG2, IgG3 and IgG4 but not to IgG1. Binding is mediated through interactions between domains 1-3 of Ply and the Fab region of the IgGs. An additional aim of this thesis was to investigate pore formation by Ply. The crystal structure of Ply, determined in our group, showed that Ply monomers in the crystal pack together similar to the way in which they are likely to assemble on the cell surface prior to pore formation. Based on the structure, a series of mutations were created to disrupt packing between Ply monomers during pre-pore and pore formation. The activities of two of the mutants, Asp205Arg and Asn339Arg were completely abolished and most of the mutants had greatly reduced activities compared to wild-type Ply indicating that these residues play important roles during pore formation. Interestingly, electron microscopy showed that Ply Asp205Arg forms chain like structures on membranes but cannot form circular pores or arcs. Thus although monomers still self-associated they could not kill cells. By contrast, Ply Asn339Arg, binds to the membrane but does not oligomerize. In further work, crystal structures of the membrane-binding domain of Ply revealed conformational changes in a Trp rich-loop at the base of the toxin involved in membrane binding. These changes promote new packing interactions between Ply monomer thereby promoting oligomerization on the membrane. Finally, I investigated the structural changes of the membrane by spectroscopic monitoring of optically trapped vesicles. The inelastic back-scattered light was monitored from a single liposome, held by optical tweezers and exposed to Ply. Ply binding increased the membrane fluidity due to a decrease in the short-range order of the lipid molecules in the bilayer. Analysis of a series of point mutants suggests that these changes are caused by association of Ply monomers during formation of the pre-pore, prior to insertion across the membrane.
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Moser, Rebekka. "IgG Antiköperbestimmung gegen Haemophilus influenza Typ b, Streptococcus pneumoniae Stereotypen 14 und 19F und Clostridium tetani Toxin in Nabelschnurseren und Seren von 0-6 Monate alten Säuglingen /." [S.l.] : [s.n.], 1998. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.
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Yesilkaya, Hasan. "Studies on the role of superoxide dismutase (SOD) in the virulence of Streptococcus pneumoniae and the effects of interferon gamma on sensitivity of phagocytes to the toxin pneumolyin." Thesis, University of Leicester, 1999. http://hdl.handle.net/2381/29803.
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The major point of the study was into how the penumococcus copes with reactive derivatives of oxygen. Superoxide dismutase is one of the enzymes that provides protection against deleterious effects of superoxide radical by conversion of superoxide to hydrogen peroxide and molecular oxygen. In this study, it was shown that S. pneumoniae contains two types of superoxide dismutase, MnSOD and FeSOD. While the level of MnSOD increased during growth in an aerobic environment, the amount of FeSOD remained unchanged. An isogenic sodA insertion-mutant strain of S. pneumoniae was constructed to study the role for the enzyme in vitro and in vivo. Aerobically the mutant strain of S. pneumoniae, designated as D39HY1, had a lower growth rate than the wild type and exhibited susceptibility to the redox active compound, paraquat. Anaerobic growth of D39HY1 was identical to the wild-type. Virulence studies showed that the median survival time of mice infected intranasally with D39HY1 was significantly longer than mice infected with the wild type pneumococcus. In contrast to the wild-type, D39HY1 did not multiply in lungs during the first 24h but thereafter grew at the same rate as the wild-type. Appearance in the bloodstream also was delayed but growth in the blood was unimpaired by the sodA mutation. The aim of the second project was to assess whether IFN- may enhance resistance of macrophages to the deleterious effects of bacterial products. To assess this possibility, the effects of interferon gamma on sensitivity of phagocytes to the toxin pneumolysin, an important virulence determinant of S. pneumoniae, was tested by employing respiratory burst as an assay of sublytic effects. It was observed that IFN- can alter the susceptibility of cells to the lytic effect of pneumolysin. Also the respiratory burst of IFN- treated cells was insensitive to sublytic concentrations of pneumolysin.
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Cockeran, Riana. "Effects of sub-lethal concentrations of pneumolysin on the proinflammatory activities of human neutrophils in vitro." Thesis, 2003. http://hdl.handle.net/2263/28021.
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The Streptococcus pneumoniae-derived toxin, pneumolysin, has been reported to augment neutrophil-mediated inflammatory responses in murine models of experimental infection of the airways, and to favour invasive pneumococcal disease. The laboratory research presented in this thesis has been designed to investigate the possible proinflammatory interactions of pneumolysin with human neutrophils in vitro, as well as the underlying mechanisms of these. Addition of pneumolysin (0.0167 - 41.75 ng/ml) to neutrophils caused dose-related enhancement of the following proinflammatory activities of these cells: superoxide generation, elastase release, expression of the β2-integrin CR3, phospholipase A2 activity and production of leukotriene B4 and prostaglandin E2, oxidative inactivation of α-1-proteinase inhibitor, and synthesis and release of interleukin-8. Pneumolysin-mediated enhancement of these neutrophil activities was observed in the absence of detectable cytotoxicity and was most striking when the toxin was added together with the bacterial chemoattractant N-formyI-L-methionyl-L-leucyl-L-pnenylalanine (FMLP, 1 µM). Treatment of neutrophils with pneumolysin also resulted in uncontrolled influx of Ca2+ into the cells in the setting of membrane depolarisation and efflux of K+, which appeared to be a consequence of the pore forming actions of the toxin. Importantly, the proinflammatory interactions of pneumolysin with neutrophils were completely attenuated by exclusion of Ca2+ from the cell-suspending medium. These observations identify novel proinflammatory properties of pneumolysin which result from pore formation in the plasma membrane, influx of Ca2+ and augmentation of Ca2+ -activitable neutrophil functions.Thesis (DPhil)--University of Pretoria, 2005.
Immunology
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Halle, Annett [Verfasser]. "Streptococcus pneumoniae induziert Apoptose in zerebralen Endothelzellen : die Rolle bakterieller Toxine / von Annett Halle." 2005. http://d-nb.info/974139165/34.
Full textBooks on the topic "Streptococcus pneumoniae toxins"
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Noris, Marina, and Tim Goodship. The patient with haemolytic uraemic syndrome/thrombotic thrombocytopenic purpura. Edited by Giuseppe Remuzzi. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0174.
Full textAbstract:
The patient who presents with microangiopathic haemolytic anaemia, thrombocytopenia, and evidence of acute kidney injury presents a diagnostic and management challenge. Haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are two of the conditions that frequently present with this triad. They are characterized by low platelet count with normal or near-normal coagulation tests, anaemia, and signs of intravascular red cell fragmentation on blood films, and high LDH levels.HUS associated with shiga-like toxins produced usually by E.coli (typically O157 strains) may occur in outbreaks or sporadically, with geographical variations in incidence. It is predominantly a disease of young children in which painful blood diarrhoea in a minority of infected patients is succeeded by microangiopathy and acute kidney injury. Management is supportive and recovery is usual, although permanent renal damage may lead to later deterioration. Older patients may be affected and tend to have worse outcomes. Neuraminidase-producing Streptococcus pneumoniae infections (usually pneumonia) very rarely cause a similar HUS.Atypical HUS occurs sporadically and is increasingly associated with defects in the regulation of the complement pathway, either genetic or autoimmune-caused. It may respond to plasma exchange for fresh frozen plasma. Recurrences are common, including after transplantation.TTP is associated with more neurological disease and less renal involvement, but HUS and TTP overlap substantially in their manifestations. The underlying problem is in von Willebrand factor (vWF) cleavage. The plasma metalloprotease ADAMTS13 is responsible for cleaving vWF multimers, a process that is important to prevent thrombosis in the microvasculature. Autoantibodies or rarely genetic deficiency may impair this process. Plasma exchange may remove antibodies and replenish the protease.
Book chapters on the topic "Streptococcus pneumoniae toxins"
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Boulnois, G. J., T. Mitchell, K. Saunders, X. Mendez, and P. Andrew. "Structure, Function and Role in Disease of Pneumolysin, The Thiol-Activated Toxin of Streptococcus Pneumoniae." In Microbial Surface Components and Toxins in Relation to Pathogenesis, 161–69. Boston, MA: Springer US, 1991. http://dx.doi.org/10.1007/978-1-4684-8995-8_18.
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Chan, Wai Ting, Inma Moreno-Córdoba, Chew Chieng Yeo, and Manuel Espinosa. "Toxin-Antitoxin Loci in Streptococcus pneumoniae." In Prokaryotic Toxin-Antitoxins, 315–39. Berlin, Heidelberg: Springer Berlin Heidelberg, 2012. http://dx.doi.org/10.1007/978-3-642-33253-1_18.
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Tiber, Simon. "Upper and Lower Respiratory Tract Infections." In Tutorial Topics in Infection for the Combined Infection Training Programme. Oxford University Press, 2019. http://dx.doi.org/10.1093/oso/9780198801740.003.0040.
Full textAbstract:
Pharyngitis is common with incidence peaking from autumn to spring. Respiratory viruses are most commonly implicated, and are generally self-limiting conditions not requiring diagnostic workup or treatment. Bacterial pharyngitis is less common, is spread by droplets or direct transmission, and Streptococcus pyogenes (Group A strep, or GAS) is the most frequent cause. Haemophilus influenzae, Mycoplasma pneumoniae, and Neisseria gonorrhoeae are less frequent causes. Rapid antigen detection tests make the point-of-care assessment of GAS pharyngitis possible, although a negative test does not exclude infection. No method can distinguish oropharyngeal colonization from actual infection, but culture can obtain antibiotic susceptibility testing. Suspicion of infection with Neisseria gonorrhoeae, Bordetella pertussis, Haemophilus influenzae, Mycoplasma pneumoniae, Chlamydophila pneumoniae, or Corynebacterium diptheriae should be communicated to the laboratory so that the appropriate culture media is utilized. The Centor criteria provide a clinical predictive score that can give the likelihood a sore throat is due to a bacterial infection with the following: the presence of tonsillar exudate, tender anterior cervical adenopathy, fever over 38°C, and absence of cough. If three or four of these criteria are met, the positive predictive value is 40% to 60%. The absence of three or four of the Centor criteria has a relatively high negative predictive value of 80%, and may be use to evaluate whether antibiotics can be withheld or deferred. Oral penicillin or macrolide are used to treat streptococcal pharyngitis. Treatment may reduce severity, duration, transmission, and risk of post-infectious sequelae like rheumatic heart disease and post-streptococcal glomerulonephritis. Other complications include scarlet fever, streptococcal toxic shock syndrome, and quinsy. Otitis media, is frequent in the young children, possibly due to a short and horizontal Eustachian tube. Purulent material buils up leading to a bulging, red tympanic membrane which may rupture and discharge. Intense local pain and fevers may occur. Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae are frequently implicated. Frequently there are no sequelae, although complications include hearing impairment, and less common are mastoiditis, bacteraemia, and meningitis. Diagnosis is clinical based on presentation and otoscopic examination. Microbiological diagnosis is possible through culture of exuate on swab or following tympanocentesis.