Journal articles: '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.

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Beno, Sarah M., Ashleigh N. Riegler, Ryan P. Gilley, Terry Brissac, Yong Wang, Katherine L. Kruckow, Jeevan K. Jadapalli, et al. "Inhibition of Necroptosis to Prevent Long-term Cardiac Damage During Pneumococcal Pneumonia and Invasive Disease." Journal of Infectious Diseases 222, no. 11 (June 3, 2020): 1882–93. http://dx.doi.org/10.1093/infdis/jiaa295.

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Abstract Background Streptococcus pneumoniae infection can result in bacteremia with devastating consequences including heart damage. Necroptosis is a proinflammatory form of cell death instigated by pore-forming toxins such as S. pneumoniae pneumolysin. Necroptosis-inhibiting drugs may lessen organ damage during invasive pneumococcal disease (IPD). Methods In vitro experiments were carried out with human and mouse cardiomyocytes. Long-term cardiac damage was assessed using high-resolution echocardiography in ampicillin-rescued mice 3 months after challenge with S. pneumoniae. Ponatinib, a necroptosis-inhibiting and Food and Drug Administration–approved drug for lymphocytic leukemia treatment, was administered intraperitoneally alongside ampicillin to test its therapeutic efficacy. Histology of heart sections included hematoxylin-eosin staining for overt damage, immunofluorescence for necroptosis, and Sirius red/fast green staining for collagen deposition. Results Cardiomyocyte death and heart damage was due to pneumolysin-mediated necroptosis. IPD leads to long-term cardiac damage, as evidenced by de novo collagen deposition in mouse hearts and a decrease in fractional shortening. Adjunct necroptosis inhibition reduced the number of S. pneumoniae foci observed in hearts of acutely infected mice and serum levels of troponin I. Ponatinib reduced collagen deposition and protected heart function in convalescence. Conclusions Acute and long-term cardiac damage incurred during IPD is due in part to cardiomyocyte necroptosis. Necroptosis inhibitors may be a viable adjunct therapy.

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Kucinskaite-Kodze, Indre, Martynas Simanavicius, Justas Dapkunas, Milda Pleckaityte, and Aurelija Zvirbliene. "Mapping of Recognition Sites of Monoclonal Antibodies Responsible for the Inhibition of Pneumolysin Functional Activity." Biomolecules 10, no. 7 (July 8, 2020): 1009. http://dx.doi.org/10.3390/biom10071009.

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The pathogenicity of many bacteria, including Streptococcus pneumoniae, depends on pore-forming toxins (PFTs) that cause host cell lysis by forming large pores in cholesterol-containing cell membranes. Therefore, PFTs-neutralising antibodies may provide useful tools for reducing S. pneumoniae pathogenic effects. This study aimed at the development and characterisation of monoclonal antibodies (MAbs) with neutralising activity to S. pneumoniae PFT pneumolysin (PLY). Five out of 10 produced MAbs were able to neutralise the cytolytic activity of PLY on a lung epithelial cell line. Epitope mapping with a series of recombinant overlapping PLY fragments revealed that neutralising MAbs are directed against PLY loops L1 and L3 within domain 4. The epitopes of MAbs 3A9, 6E5 and 12F11 located at L1 loop (aa 454–471) were crucial for PLY binding to the immobilised cholesterol. In contrast, the MAb 12D10 recognising L3 (aa 403–423) and the MAb 3F3 against the conformational epitope did not interfere with PLY-cholesterol interaction. Due to conformation-dependent binding, the approach to use overlapping peptides for fine epitope mapping of the neutralising MAbs was unsuccessful. Therefore, the epitopes recognised by the MAbs were analysed using computational methods. This study provides new data on PLY sites involved in functional activity.

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Pimenta, F. C., E. N. Miyaji, A. P. M. Arêas, M. L. S. Oliveira, A. L. S. S. de Andrade, P. L. Ho, S. K. Hollingshead, and L. C. C. Leite. "Intranasal Immunization with the Cholera Toxin B Subunit-Pneumococcal Surface Antigen A Fusion Protein Induces Protection against Colonization with Streptococcus pneumoniae and Has Negligible Impact on the Nasopharyngeal and Oral Microbiota of Mice." Infection and Immunity 74, no. 8 (August 2006): 4939–44. http://dx.doi.org/10.1128/iai.00134-06.

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ABSTRACT One of the candidate proteins for a mucosal vaccine antigen against Streptococcus pneumoniae is PsaA (pneumococcal surface antigen A). Vaccines targeting mucosal immunity may raise concerns as to possible alterations in the normal microbiota, especially in the case of PsaA, which was shown to have homologs with elevated sequence identity in other viridans group streptococci. In this work, we demonstrate that intranasal immunization with a cholera toxin B subunit-PsaA fusion protein is able to protect mice against colonization with S. pneumoniae but does not significantly alter the natural oral or nasopharyngeal microbiota of mice.

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Kay, Emily J., Laura E. Yates, Vanessa S. Terra, Jon Cuccui, and Brendan W. Wren. "Recombinant expression of Streptococcus pneumoniae capsular polysaccharides in Escherichia coli." Open Biology 6, no. 4 (April 2016): 150243. http://dx.doi.org/10.1098/rsob.150243.

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Currently, Streptococcus pneumoniae is responsible for over 14 million cases of pneumonia worldwide annually, and over 1 million deaths, the majority of them children. The major determinant for pathogenesis is a polysaccharide capsule that is variable and is used to distinguish strains based on their serotype. The capsule forms the basis of the pneumococcal polysaccharide vaccine (PPV23) that contains purified capsular polysaccharide from 23 serotypes, and the pneumococcal conjugate vaccine (PCV13), containing 13 common serotypes conjugated to CRM197 (mutant diphtheria toxin). Purified capsule from S. pneumoniae is required for pneumococcal conjugate vaccine production, and costs can be prohibitively high, limiting accessibility of the vaccine in low-income countries. In this study, we demonstrate the recombinant expression of the capsule-encoding locus from four different serotypes of S. pneumoniae within Escherichia coli . Furthermore, we attempt to identify the minimum set of genes necessary to reliably and efficiently express these capsules heterologously. These E. coli strains could be used to produce a supply of S. pneumoniae serotype-specific capsules without the need to culture pathogenic bacteria. Additionally, these strains could be applied to synthetic glycobiological applications: recombinant vaccine production using E. coli outer membrane vesicles or coupling to proteins using protein glycan coupling technology.

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Kirkham, Lea-Ann S., Alison R. Kerr, Gill R. Douce, Gavin K. Paterson, Deborah A. Dilts, Dai-Fang Liu, and Tim J. Mitchell. "Construction and Immunological Characterization of a Novel Nontoxic Protective Pneumolysin Mutant for Use in Future Pneumococcal Vaccines." Infection and Immunity 74, no. 1 (January 2006): 586–93. http://dx.doi.org/10.1128/iai.74.1.586-593.2006.

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ABSTRACT Pneumolysin, the pore-forming toxin produced by Streptococcus pneumoniae, may have an application as an immunogenic carrier protein in future pneumococcal conjugate vaccines. Most of the 90 S. pneumoniae serotypes identified produce pneumolysin; therefore, this protein may confer non-serotype-specific protection against pneumococcal infections such as pneumonia, meningitis, and otitis media. However, as pneumolysin is highly toxic, a nontoxic form of pneumolysin would be a more desirable starting point in terms of vaccine production. Previous pneumolysin mutants have reduced activity but retain residual toxicity. We have found a single amino acid deletion that blocks pore formation, resulting in a form of pneumolysin that is unable to form large oligomeric ring structures. This mutant is nontoxic at concentrations greater than 1,000 times that of the native toxin. We have demonstrated that this mutant is as immunogenic as native pneumolysin without the associated effects such as production of the inflammatory mediators interleukin-6 and cytokine-induced neutrophil chemoattractant KC, damage to lung integrity, and hypothermia in mice. Vaccination with this mutant protects mice from challenge with S. pneumoniae. Incorporation of this mutant pneumolysin into current pneumococcal vaccines may increase their efficacy.

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Duong, Michel, Marie Simard, Yves Bergeron, and Michel G. Bergeron. "Kinetic Study of the Inflammatory Response in Streptococcus pneumoniae Experimental Pneumonia Treated with the Ketolide HMR 3004." Antimicrobial Agents and Chemotherapy 45, no. 1 (January 1, 2001): 252–62. http://dx.doi.org/10.1128/aac.45.1.252-262.2001.

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ABSTRACT Patients still die from Streptococcus pneumoniaepneumonia after initiation of antibiotic therapy, when tissues are sterile and the pneumonia is clearing. There is growing evidence that overwhelming inflammation resulting from toxin release contributes to tissue injury, shock, and death. Monitoring host response may help us understand the consequences of antibiotic therapy for the inflammatory processes that occur in bacterial pneumonia. HMR 3004 is a ketolide that displays excellent in vitro activity against S. pneumoniae. In the present experiment, we investigated the chronology of inflammatory events that occur during pneumococcal pneumonia in mice treated with HMR 3004. Infection of mice with 107 CFU of living S. pneumoniae resulted in 100% mortality within 5 days. HMR 3004 given at 12.5 mg/kg of body weight/dose twice daily from 48 h postinfection achieved complete bacterial clearance from lungs and blood within 36 h and ensured survival of mice. Recruitment of neutrophils and monocytes from blood to lungs was significantly reduced, and nitric oxide release was totally prevented. Interleukin-6 secretion in lungs and blood became rapidly undetectable after initiation of therapy. Histological examination of lung tissue showed protection of interstitium against edema. By controlling bacterial invasion, HMR 3004 led to rapid and profound modifications of the host response in lungs, which may protect mice from deleterious inflammatory reactions.

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Inomata, Megumi, Shuying Xu, Pallavi Chandra, Simin N. Meydani, Genzou Takemura, Jennifer A. Philips, and John M. Leong. "Macrophage LC3-associated phagocytosis is an immune defense against Streptococcus pneumoniae that diminishes with host aging." Proceedings of the National Academy of Sciences 117, no. 52 (December 21, 2020): 33561–69. http://dx.doi.org/10.1073/pnas.2015368117.

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Streptococcus pneumoniae is a leading cause of pneumonia and invasive disease, particularly, in the elderly. S. pneumoniae lung infection of aged mice is associated with high bacterial burdens and detrimental inflammatory responses. Macrophages can clear microorganisms and modulate inflammation through two distinct lysosomal trafficking pathways that involve 1A/1B-light chain 3 (LC3)-marked organelles, canonical autophagy, and LC3-associated phagocytosis (LAP). The S. pneumoniae pore-forming toxin pneumolysin (PLY) triggers an autophagic response in nonphagocytic cells, but the role of LAP in macrophage defense against S. pneumoniae or in age-related susceptibility to infection is unexplored. We found that infection of murine bone-marrow-derived macrophages (BMDMs) by PLY-producing S. pneumoniae triggered Atg5- and Atg7-dependent recruitment of LC3 to S. pneumoniae-containing vesicles. The association of LC3 with S. pneumoniae-containing phagosomes required components specific for LAP, such as Rubicon and the NADPH oxidase, but not factors, such as Ulk1, FIP200, or Atg14, required specifically for canonical autophagy. In addition, S. pneumoniae was sequestered within single-membrane compartments indicative of LAP. Importantly, compared to BMDMs from young (2-mo-old) mice, BMDMs from aged (20- to 22-mo-old) mice infected with S. pneumoniae were not only deficient in LAP and bacterial killing, but also produced higher levels of proinflammatory cytokines. Inhibition of LAP enhanced S. pneumoniae survival and cytokine responses in BMDMs from young but not aged mice. Thus, LAP is an important innate immune defense employed by BMDMs to control S. pneumoniae infection and concomitant inflammation, one that diminishes with age and may contribute to age-related susceptibility to this important pathogen.

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Periselneris, Jimstan, Mahdad Noursadeghi, and Jeremy Brown. "Anti-inflammatory effects of Streptococcus pneumoniae toxin pneumolysin." Lancet 387 (February 2016): S80. http://dx.doi.org/10.1016/s0140-6736(16)00467-0.

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Jounblat, Rania, Aras Kadioglu, Tim J. Mitchell, and Peter W. Andrew. "Pneumococcal Behavior and Host Responses during Bronchopneumonia Are Affected Differently by the Cytolytic and Complement-Activating Activities of Pneumolysin." Infection and Immunity 71, no. 4 (April 2003): 1813–19. http://dx.doi.org/10.1128/iai.71.4.1813-1819.2003.

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ABSTRACT Pneumolysin, a multifunctional toxin produced by all clinical isolates of Streptococcus pneumoniae, is strongly implicated in the pathogenesis of pneumococcal bronchopneumonia and septicemia. Using isogenic mutant strains, we examined the effect of deletion of the cytotoxic activity or complement-activating activity of pneumolysin on bacterial growth in lungs and blood, histological changes in infected lung tissue, and the pattern of inflammatory cell recruitment. Both of the activities of pneumolysin contributed to the pathology in the lungs, as well as the timing of the onset of bacteremia. Histological changes in the lungs were delayed after infection with either mutant compared to the changes seen after infection with the wild-type pneumococcus. The complement-activating activity of pneumolysin affected the accumulation of T cells, whereas the toxin's cytolytic activity influenced neutrophil recruitment into lung tissue.

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Jahn, Kristin, Stefan Handtke, Raghavendra Palankar, Sabrina Weißmüller, Geraldine Nouailles, Thomas P. Kohler, Jan Wesche, et al. "Pneumolysin induces platelet destruction, not platelet activation, which can be prevented by immunoglobulin preparations in vitro." Blood Advances 4, no. 24 (December 18, 2020): 6315–26. http://dx.doi.org/10.1182/bloodadvances.2020002372.

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Abstract Community-acquired pneumonia by primary or superinfections with Streptococcus pneumoniae can lead to acute respiratory distress requiring mechanical ventilation. The pore-forming toxin pneumolysin alters the alveolar-capillary barrier and causes extravasation of protein-rich fluid into the interstitial pulmonary tissue, which impairs gas exchange. Platelets usually prevent endothelial leakage in inflamed pulmonary tissue by sealing inflammation-induced endothelial gaps. We not only confirm that S pneumoniae induces CD62P expression in platelets, but we also show that, in the presence of pneumolysin, CD62P expression is not associated with platelet activation. Pneumolysin induces pores in the platelet membrane, which allow anti-CD62P antibodies to stain the intracellular CD62P without platelet activation. Pneumolysin treatment also results in calcium efflux, increase in light transmission by platelet lysis (not aggregation), loss of platelet thrombus formation in the flow chamber, and loss of pore-sealing capacity of platelets in the Boyden chamber. Specific anti-pneumolysin monoclonal and polyclonal antibodies inhibit these effects of pneumolysin on platelets as do polyvalent human immunoglobulins. In a post hoc analysis of the prospective randomized phase 2 CIGMA trial, we show that administration of a polyvalent immunoglobulin preparation was associated with a nominally higher platelet count and nominally improved survival in patients with severe S pneumoniae–related community-acquired pneumonia. Although, due to the low number of patients, no definitive conclusion can be made, our findings provide a rationale for investigation of pharmacologic immunoglobulin preparations to target pneumolysin by polyvalent immunoglobulin preparations in severe community-acquired pneumococcal pneumonia, to counteract the risk of these patients becoming ventilation dependent. This trial was registered at www.clinicaltrials.gov as #NCT01420744.

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Blue, C. E., G. K. Paterson, A. R. Kerr, M. Bergé, J. P. Claverys, and T. J. Mitchell. "ZmpB, a Novel Virulence Factor of Streptococcus pneumoniae That Induces Tumor Necrosis Factor Alpha Production in the Respiratory Tract." Infection and Immunity 71, no. 9 (September 2003): 4925–35. http://dx.doi.org/10.1128/iai.71.9.4925-4935.2003.

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ABSTRACT Inflammation is a prominent feature of Streptococcus pneumoniae infection in both humans and animal models. Indeed, an intense host immune response to infection is thought to contribute significantly to the pathology of pneumococcal pneumonia and meningitis. Previously, induction of the inflammatory response following infection with S. pneumoniae has been attributed to certain cell wall constituents and the toxin pneumolysin. Here we present data implicating a putative zinc metalloprotease, ZmpB, as having a role in inflammation. Null mutations were created in the zmpB gene of the virulent serotype 2 strain D39 and analyzed in a murine model of infection. Isogenic mutants were attenuated in pneumonia and septicemia models of infection, as determined by levels of bacteremia and murine survival. Mutants were not attenuated in colonization of murine airways or lung tissue. Examination of cytokine profiles within the lung tissue revealed significantly lower levels of the proinflammatory cytokine tumor necrosis factor alpha following challenge with the ΔzmpB mutant (Δ739). These data identify ZmpB as a novel virulence factor capable of inducing inflammation in the lower respiratory tract. The possibility that ZmpB was involved in inhibition of complement activity was examined, but the data indicated that ZmpB does not have a significant effect on this important host defense. The regulation of ZmpB by a two-component system (TCS09) located immediately upstream of the zmpB gene was examined. TCS09 was not required for the expression of zmpB during exponential growth in vitro.

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Ochigava, Irma, Phillip J. Collier, Graeme M. Walker, and Regine Hakenbeck. "Williopsis saturnus yeast killer toxin does not kill Streptococcus pneumoniae." Antonie van Leeuwenhoek 99, no. 3 (October 22, 2010): 559–66. http://dx.doi.org/10.1007/s10482-010-9524-3.

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Malley, Richard, Sarah C. Morse, Luciana C. C. Leite, Ana Paula Mattos Areas, Paulo Lee Ho, Flavia S. Kubrusly, Igor C. Almeida, and Porter Anderson. "Multiserotype Protection of Mice against Pneumococcal Colonization of the Nasopharynx and Middle Ear by Killed Nonencapsulated Cells Given Intranasally with a Nontoxic Adjuvant." Infection and Immunity 72, no. 7 (July 2004): 4290–92. http://dx.doi.org/10.1128/iai.72.7.4290-4292.2004.

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ABSTRACT Intranasal challenge of C57BL/6 mice with Streptococcus pneumoniae serotypes 6B, 14, and 23F produced colonization of the middle ear and NP. Intranasal vaccination with ethanol-killed nonencapsulated cells with adjuvant protected both sites. Of four nontoxic adjuvants tested, the cholera toxin B subunit was most effective and least nonspecifically protective.

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Maatsola, Santeri, Sami Kurkinen, Marica T. Engström, Thomas K. M. Nyholm, Olli Pentikäinen, Juha-Pekka Salminen, and Sauli Haataja. "Inhibition of Pneumolysin Cytotoxicity by Hydrolysable Tannins." Antibiotics 9, no. 12 (December 21, 2020): 930. http://dx.doi.org/10.3390/antibiotics9120930.

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Streptococcus pneumoniae causes invasive infections such as otitis media, pneumonia and meningitis. It produces the pneumolysin (Ply) toxin, which forms a pore onto the host cell membrane and has multiple functions in the pathogenesis of S. pneumoniae. The Ply C-terminal domain 4 mediates binding to membrane cholesterol and induces the formation of pores composed of up to 40 Ply monomers. Ply has a key role in the establishment of nasal colonization, pneumococcal transmission from host to host and pathogenicity. Altogether, 27 hydrolysable tannins were tested for Ply inhibition in a hemolysis assay and a tannin-protein precipitation assay. Pentagalloylglucose (PGG) and gemin A showed nanomolar inhibitory activity. Ply oligomerization on the erythrocyte surface was inhibited with PGG. PGG also inhibited Ply cytotoxicity to A549 human lung epithelial cells. Molecular modelling of Ply interaction with PGG suggests that it binds to the pocket formed by domains 2, 3 and 4. In this study, we reveal the structural features of hydrolysable tannins that are required for interaction with Ply. Monomeric hydrolysable tannins containing three to four flexible galloyl groups have the highest inhibitory power to Ply cytotoxicity and are followed by oligomers. Of the oligomers, macrocyclic and C-glycosidic structures were weaker in their inhibition than the glucopyranose-based oligomers. Accordingly, PGG-type monomers and oligomers might have therapeutic value in the targeting of S. pneumoniae infections.

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Jefferies, Johanna, Leena Nieminen, Lea-Ann Kirkham, Calum Johnston, Andrew Smith, and Tim J. Mitchell. "Identification of a Secreted Cholesterol-Dependent Cytolysin (Mitilysin) from Streptococcus mitis." Journal of Bacteriology 189, no. 2 (October 27, 2006): 627–32. http://dx.doi.org/10.1128/jb.01092-06.

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ABSTRACT We have detected a cholesterol-dependent cytolysin, which we have named mitilysin, in a small number of Streptococcus mitis isolates. We have sequenced the mitilysin gene from seven isolates of S. mitis. Comparisons with the pneumococcal pneumolysin gene show 15 amino acid substitutions. S. mitis appear to release mitilysin extracellularly. Certain alleles of mitilysin are not recognized by a monoclonal antibody raised to the related toxin pneumolysin. Based on enzyme-linked immunosorbent assay and neutralization assay results, one isolate of S. mitis may produce a further hemolytic toxin in addition to mitilysin. As genetic exchange is known to occur between S. mitis and Streptococcus pneumoniae, this finding may have implications for the development of vaccines or therapies for pneumococcal disease that are based on pneumolysin.

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Balachandran, Priya, Alexis Brooks-Walter, Anni Virolainen-Julkunen, Susan K. Hollingshead, and David E. Briles. "Role of Pneumococcal Surface Protein C in Nasopharyngeal Carriage and Pneumonia and Its Ability To Elicit Protection against Carriage of Streptococcus pneumoniae." Infection and Immunity 70, no. 5 (May 2002): 2526–34. http://dx.doi.org/10.1128/iai.70.5.2526-2534.2002.

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ABSTRACT Previous studies suggested that PspC is important in adherence and colonization within the nasopharynx. In this study, we conducted mutational studies to further identify the role PspC plays in the pathogenesis of pneumococci. pspC and/or pspA was insertionally inactivated in a serotype 2 Streptococcus pneumoniae strain and in a serotype 19 S. pneumoniae strain. In the mouse colonization model, pneumococcal strains with mutations in pspC were significantly attenuated in their abilities to colonize. In a mouse pneumonia model, strains with mutations in pspC were unable to infect or multiply within the lung. Using reverse transcriptase PCR we were able to demonstrate that pspC is actively transcribed in vivo, when the bacteria are growing in the nasal cavity and in the lungs. In the bacteremia model, a strain mutated for pspC alone behaved like the wild type, but the absence of both pspC and pspA caused accelerated clearance of the bacteria. Intranasal immunization with PspC with cholera toxin subunit B as an adjuvant protected against intranasal challenge. Evidence was also obtained that revertants that spontaneously acquired PspC expression could multiply and colonize the nasal tissue. This latter finding strongly indicates that pneumococci are actively metabolizing and growing while in the nasopharynx.

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Chan, Wai, Mirian Domenech, Inmaculada Moreno-Córdoba, Verónica Navarro-Martínez, Concha Nieto, Miriam Moscoso, Ernesto García, and Manuel Espinosa. "The Streptococcus pneumoniae yefM-yoeB and relBE Toxin-Antitoxin Operons Participate in Oxidative Stress and Biofilm Formation." Toxins 10, no. 9 (September 18, 2018): 378. http://dx.doi.org/10.3390/toxins10090378.

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Type II (proteic) toxin-antitoxin systems (TAs) are widely distributed among bacteria and archaea. They are generally organized as operons integrated by two genes, the first encoding the antitoxin that binds to its cognate toxin to generate a harmless protein–protein complex. Under stress conditions, the unstable antitoxin is degraded by host proteases, releasing the toxin to achieve its toxic effect. In the Gram-positive pathogen Streptococcus pneumoniae we have characterized four TAs: pezAT, relBE, yefM-yoeB, and phD-doc, although the latter is missing in strain R6. We have assessed the role of the two yefM-yoeB and relBE systems encoded by S. pneumoniae R6 by construction of isogenic strains lacking one or two of the operons, and by complementation assays. We have analyzed the phenotypes of the wild type and mutants in terms of cell growth, response to environmental stress, and ability to generate biofilms. Compared to the wild-type, the mutants exhibited lower resistance to oxidative stress. Further, strains deleted in yefM-yoeB and the double mutant lacking yefM-yoeB and relBE exhibited a significant reduction in their ability for biofilm formation. Complementation assays showed that defective phenotypes were restored to wild type levels. We conclude that these two loci may play a relevant role in these aspects of the S. pneumoniae lifestyle and contribute to the bacterial colonization of new niches.

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Berry, Anne M., A. David Ogunniyi, David C. Miller, and James C. Paton. "Comparative Virulence of Streptococcus pneumoniaeStrains with Insertion-Duplication, Point, and Deletion Mutations in the Pneumolysin Gene." Infection and Immunity 67, no. 2 (February 1, 1999): 981–85. http://dx.doi.org/10.1128/iai.67.2.981-985.1999.

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ABSTRACT Pneumolysin is a 471-amino-acid toxin produced byStreptococcus pneumoniae which has both cytolytic and complement activation properties. We have constructed a derivative of the type 2 S. pneumoniae strain D39 in which the portion of the pneumolysin gene encoding amino acids 55 to 437 has been deleted in-frame. The virulence of this strain (ΔPly) was compared with those of wild-type D39, a pneumolysin insertion-duplication mutant (PLN-A), and a derivative (PdT) carrying a toxin gene with three point mutations known to abolish both cytolytic activity and complement activation. PdT was intermediate in virulence between D39 and either PLN-A or ΔPly in a mouse intraperitoneal challenge model. This provides unequivocal evidence that pneumolysin has an additional property that is not abolished by point mutations which reduce cytotoxicity and complement activation to virtually undetectable levels.

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Hirst, Robert A., Hasan Yesilkaya, Edwin Clitheroe, Andrew Rutman, Nichola Dufty, Timothy J. Mitchell, Christopher O’Callaghan, and Peter W. Andrew. "Sensitivities of Human Monocytes and Epithelial Cells to Pneumolysin Are Different." Infection and Immunity 70, no. 2 (February 2002): 1017–22. http://dx.doi.org/10.1128/iai.70.2.1017-1022.2002.

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ABSTRACT The Streptococcus pneumoniae pore-forming toxin, pneumolysin, is an important virulence factor in pneumococcal pneumonia. The effect of pneumolysin on human lung epithelial and monocyte cell viability was compared. Pneumolysin caused a dose-dependent loss of viability of human lung epithelial (A549 and L132) and monocyte (U937 and THP-1) cell lines. Analysis of the dose-response curves revealed similar log 50% inhibitory concentration (pIC50) values for A549, L132, and THP-1 of 0.12± 0.1, 0.02± 0.04, and 0.12± 0.13 hemolytic units (HU), respectively, but U937 cells showed a significantly greater pIC50 of 0.42± 0.12 HU. Differentiation of A549 and L132 with phorbol ester or THP-1 with gamma interferon had no effect on their sensitivity to pneumolysin. However, a significant decrease in the potency of pneumolysin against U937 cells followed gamma interferon treatment. The Hill slopes of the inhibition curves were greater than unity, indicating that pneumolysin may act with positive cooperativity. Analysis of pneumolysin-treated THP-1 cells by electron microscopy revealed membrane lesions of between 100 and 200 nm in diameter.

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Mingoia, Marina, Eleonora Morici, Gianluca Morroni, Eleonora Giovanetti, Maria Del Grosso, Annalisa Pantosti, and Pietro E. Varaldo. "Tn5253Family Integrative and Conjugative Elements Carryingmef(I) andcatQDeterminants in Streptococcus pneumoniae and Streptococcus pyogenes." Antimicrobial Agents and Chemotherapy 58, no. 10 (July 28, 2014): 5886–93. http://dx.doi.org/10.1128/aac.03638-14.

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ABSTRACTThe linkage between the macrolide efflux genemef(I) and the chloramphenicol inactivation genecatQwas first described inStreptococcus pneumoniae(strain Spn529), where the two genes are located in a module designated IQ element. Subsequently, two different defective IQ elements were detected inStreptococcus pyogenes(strains Spy029 and Spy005). The genetic elements carrying the three IQ elements were characterized, and all were found to be Tn5253family integrative and conjugative elements (ICEs). The ICE fromS. pneumoniae(ICESpn529IQ) was sequenced, whereas the ICEs fromS. pyogenes(ICESpy029IQ and ICESpy005IQ, the first Tn5253-like ICEs reported in this species) were characterized by PCR mapping, partial sequencing, and restriction analysis. ICESpn529IQ and ICESpy029IQ were found to share theintSp23FST81integrase gene and an identical Tn916fragment, whereas ICESpy005IQ hasint5252and lacks Tn916. All three ICEs were found to lack the linearized pC194 plasmid that is usually associated with Tn5253-like ICEs, and all displayed a single copy of a toxin-antitoxin operon that is typically contained in the direct repeats flanking the excisable pC194 region when this region is present. Two different insertion sites of the IQ elements were detected, one in ICESpn529IQ and ICESpy029IQ, and another in ICESpy005IQ. The chromosomal integration of the three ICEs was site specific, depending on the integrase (intSp23FST81orint5252). Only ICESpy005IQ was excised in circular form and transferred by conjugation. By transformation,mef(I) andcatQwere cotransferred at a high frequency fromS. pyogenesSpy005 and at very low frequencies fromS. pneumoniaeSpn529 andS. pyogenesSpy029.

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Romero, Patricia, Nicholas J. Croucher, N. Luisa Hiller, Fen Z. Hu, Garth D. Ehrlich, Stephen D. Bentley, Ernesto García, and Tim J. Mitchell. "Comparative Genomic Analysis of Ten Streptococcus pneumoniae Temperate Bacteriophages." Journal of Bacteriology 191, no. 15 (June 5, 2009): 4854–62. http://dx.doi.org/10.1128/jb.01272-08.

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ABSTRACT Streptococcus pneumoniae is an important human pathogen that often carries temperate bacteriophages. As part of a program to characterize the genetic makeup of prophages associated with clinical strains and to assess the potential roles that they play in the biology and pathogenesis in their host, we performed comparative genomic analysis of 10 temperate pneumococcal phages. All of the genomes are organized into five major gene clusters: lysogeny, replication, packaging, morphogenesis, and lysis clusters. All of the phage particles observed showed a Siphoviridae morphology. The only genes that are well conserved in all the genomes studied are those involved in the integration and the lysis of the host in addition to two genes, of unknown function, within the replication module. We observed that a high percentage of the open reading frames contained no similarities to any sequences catalogued in public databases; however, genes that were homologous to known phage virulence genes, including the pblB gene of Streptococcus mitis and the vapE gene of Dichelobacter nodosus, were also identified. Interestingly, bioinformatic tools showed the presence of a toxin-antitoxin system in the phage φSpn_6, and this represents the first time that an addition system in a pneumophage has been identified. Collectively, the temperate pneumophages contain a diverse set of genes with various levels of similarity among them.

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Gilbert, Robert J. C., Jamie Rossjohn, Michael W. Parker, Rodney K. Tweten, Peter J. Morgan, Timothy J. Mitchell, Neil Errington, Arthur J. Rowe, Peter W. Andrew, and Olwyn Byron. "Self-interaction of pneumolysin, the pore-forming protein toxin of Streptococcus pneumoniae." Journal of Molecular Biology 284, no. 4 (December 1998): 1223–37. http://dx.doi.org/10.1006/jmbi.1998.2258.

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Chan, W. T., C. Nieto, J. A. Harikrishna, S. K. Khoo, R. Y. Othman, M. Espinosa, and C. C. Yeo. "Genetic Regulation of the yefM-yoeB Toxin-Antitoxin Locus of Streptococcus pneumoniae." Journal of Bacteriology 193, no. 18 (July 15, 2011): 4612–25. http://dx.doi.org/10.1128/jb.05187-11.

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Moreno-Córdoba, Inmaculada, Wai-Ting Chan, Concha Nieto, and Manuel Espinosa. "Interactions of the Streptococcus pneumoniae Toxin-Antitoxin RelBE Proteins with Their Target DNA." Microorganisms 9, no. 4 (April 15, 2021): 851. http://dx.doi.org/10.3390/microorganisms9040851.

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Type II bacterial toxin-antitoxin (TA) systems are found in most bacteria, archaea, and mobile genetic elements. TAs are usually found as a bi-cistronic operon composed of an unstable antitoxin and a stable toxin that targets crucial cellular functions like DNA supercoiling, cell-wall synthesis or mRNA translation. The type II RelBE system encoded by the pathogen Streptococcus pneumoniae is highly conserved among different strains and participates in biofilm formation and response to oxidative stress. Here, we have analyzed the participation of the RelB antitoxin and the RelB:RelE protein complex in the self-regulation of the pneumococcal relBE operon. RelB acted as a weak repressor, whereas RelE performed the role of a co-repressor. By DNA footprinting experiments, we show that the proteins bind to a region that encompasses two palindromic sequences that are located around the −10 sequences of the single promoter that directs the synthesis of the relBE mRNA. High-resolution footprinting assays showed the distribution of bases whose deoxyriboses are protected by the bound proteins, demonstrating that RelB and RelB:RelE contacted the DNA backbone on one face of the DNA helix and that these interactions extended beyond the palindromic sequences. Our findings suggest that the binding of the RelBE proteins to its DNA target would lead to direct inhibition of the binding of the host RNA polymerase to the relBE promoter.

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Braun, Johann S., Rodger Novak, Geli Gao, Peter J. Murray, and Jerry L. Shenep. "Pneumolysin, a Protein Toxin of Streptococcus pneumoniae, Induces Nitric Oxide Production from Macrophages." Infection and Immunity 67, no. 8 (August 1, 1999): 3750–56. http://dx.doi.org/10.1128/iai.67.8.3750-3756.1999.

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ABSTRACT Nitric oxide (NO) production by inducible NO synthase (iNOS) during inflammation is an essential element of antimicrobial immunity but can also contribute to host-induced tissue damage. Under conditions of bacterial sepsis, large amounts of NO are produced, causing hypotension, a critical pathological feature of septic shock. In sepsis caused by gram-positive organisms, the bacterial factors contributing to host NO production are poorly characterized. We show that a soluble toxin of Streptococcus pneumoniae, pneumolysin (Pln), is a key component initiating NO production from macrophages. In contrast to wild-type bacteria, a mutant of S. pneumoniae lacking Pln failed to elicit NO production from murine macrophages. Purified recombinant Pln induced NO production at low concentrations and independently of exogenous gamma interferon (IFN-γ) priming of RAW 264.7 macrophages. However, IFN-γ was essential for Pln-induced NO production, since primary macrophages from mice lacking the IFN-γ receptor or interferon regulatory factor 1, a transcription factor essential for iNOS expression, failed to produce NO when stimulated with Pln. In addition, Pln acts as an agonist of tumor necrosis factor alpha and interleukin 6 production in macrophages. The properties of Pln, previously identified as a pore-forming hemolysin, also include a role as a general inflammatory agonist.

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Morgan, P. J., P. G. Varley, A. J. Rowe, P. W. Andrew, and T. J. Mitchell. "Characterization of the solution properties and conformation of pneumolysin, the membrane-damaging toxin of Streptococcus pneumoniae." Biochemical Journal 296, no. 3 (December 15, 1993): 671–74. http://dx.doi.org/10.1042/bj2960671.

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Pneumolysin is a membrane-damaging toxin produced by Streptococcus pneumoniae. In order to understand fully the mode of action of this toxin, it is necessary to have an appreciation of the size, self-association behaviour and solution conformation of pneumolysin. A combination of analytical ultracentrifugation methodologies has shown that pneumolysin lacks self-association behaviour in solution and has provided a weight-average M(r) (M omega) of 52,000 +/- 2000, which was in agreement with that derived from the amino acid sequence. By determining a sedimentation coefficient (S20,w0) of 3.35 +/- 0.10 S, it was possible to suggest a model for the gross solution conformation of pneumolysin monomers. Spectroscopic methods provide additional secondary and tertiary structure information.

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Boulnois, G. J., J. C. Paton, T. J. Mitchell, and P. W. Andrew. "Structure and function of pneumolysin, the multifunctional, thiol-activated toxin of Streptococcus pneumoniae." Molecular Microbiology 5, no. 11 (November 1991): 2611–16. http://dx.doi.org/10.1111/j.1365-2958.1991.tb01969.x.

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Lu, Ying-Jie, Puja Yadav, John D. Clements, Sophie Forte, Amit Srivastava, Claudette M. Thompson, Robert Seid, et al. "Options for Inactivation, Adjuvant, and Route of Topical Administration of a Killed, Unencapsulated Pneumococcal Whole-Cell Vaccine." Clinical and Vaccine Immunology 17, no. 6 (April 28, 2010): 1005–12. http://dx.doi.org/10.1128/cvi.00036-10.

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ABSTRACT We previously reported that ethanol-killed cells of a noncapsulated strain of Streptococcus pneumoniae, given intranasally with cholera toxin as an adjuvant, protect rats against pneumonia and mice against colonization of the nasopharynx and middle ear by capsulated pneumococci of various serotypes. The acceleration of pneumococcal clearance from the nasopharynx in mice is CD4+ T cell-dependent and interleukin 17A (IL-17A) mediated and can be antibody independent. Here, anticipating human studies, we have demonstrated protection with a new vaccine strain expressing a nonhemolytic derivative of pneumolysin and grown in bovine-free culture medium. Killing the cells with chloroform, trichloroethylene, or beta-propiolactone—all used without postinactivation washing—produced more-potent immunogens than ethanol, and retention of soluble components released from the cells contributed to protection. Two sequential intranasal administrations of as little as 1 μg of protein (total of cellular and soluble combined) protected mice against nasopharyngeal challenge with pneumococci. Nontoxic single and double mutants of Escherichia coli heat-labile toxin were effective as mucosal adjuvants. Protection was induced by the sublingual and buccal routes, albeit requiring larger doses than when given intranasally. Protection was likewise induced transdermally with sonicates of the killed-cell preparation. Thus, this whole-cell antigen can be made and administered in a variety of ways to suit the manufacturer and the vaccination program and is potentially a solution to the need for a low-cost vaccine to reduce the burden of childhood pneumococcal disease in low-income countries.

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García-Suárez, María del Mar, María Dolores Cima-Cabal, Noelia Flórez, Pilar García, Rafael Cernuda-Cernuda, Aurora Astudillo, Fernando Vázquez, Juan R. De Los Toyos, and F. Javier Méndez. "Protection against Pneumococcal Pneumonia in Mice by Monoclonal Antibodies to Pneumolysin." Infection and Immunity 72, no. 8 (August 2004): 4534–40. http://dx.doi.org/10.1128/iai.72.8.4534-4540.2004.

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ABSTRACT Pneumolysin (PLY) is an important virulence factor of Streptococcus pneumoniae. We examined the ability of three murine monoclonal antibodies (MAbs) to PLY (PLY-4, PLY-5, and PLY-7) to affect the course of pneumococcal pneumonia in mice. The intravenous administration of antibodies PLY-4 and PLY-7 protected the mice from the lethal effect of the purified toxin. Mice treated with PLY-4 before intranasal inoculation of S. pneumoniae type 2 survived longer (median survival time, 100 h) than did untreated animals (median survival time, 60 h) (P < 0.0001). The median survival time for mice treated with a combination of PLY-4 and PLY-7 was 130 h, significantly longer than that for mice given isotype-matched indifferent MAbs (P = 0.0288) or nontreated mice (P = 0.0002). The median survival time for mice treated with a combination of three MAbs was significantly longer (>480 h) than that for mice treated with PLY-5 (48 h; P < 0.0001), PLY-7 (78 h; P = 0.0007), or PLY-4 (100 h; P = 0.0443) alone. Similarly, the survival rate for mice treated with three MAbs (10 of 20 mice) was significantly higher than the survival rate obtained with PLY-5 (1 of 20; P = 0.0033), PLY-4 (2 of 20; P = 0.0138), or PLY-7 (3 of 20; P = 0.0407) alone. These results suggest that anti-PLY MAbs act with a synergistic effect. Furthermore, MAb administration was associated with a significant decrease in bacterial lung colonization and lower frequencies of bacteremia and tissue injury with respect to the results for the control groups.

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Rasooly, Reuven, Hwang-Yong Choi, Paula Do, Gianluca Morroni, Lucia Brescini, Oscar Cirioni, Andrea Giacometti, and Emmanouil Apostolidis. "whISOBAXTM Inhibits Bacterial Pathogenesis and Enhances the Effect of Antibiotics." Antibiotics 9, no. 5 (May 19, 2020): 264. http://dx.doi.org/10.3390/antibiotics9050264.

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As bacteria are becoming more resistant to commonly used antibiotics, alternative therapies are being sought. whISOBAX (WH) is a witch hazel extract that is highly stable (tested up to 2 months in 37 °C) and contains a high phenolic content, where 75% of it is hamamelitannin and traces of gallic acid. Phenolic compounds like gallic acid are known to inhibit bacterial growth, while hamamelitannin is known to inhibit staphylococcal pathogenesis (biofilm formation and toxin production). WH was tested in vitro for its antibacterial activity against clinically relevant Gram-positive and Gram-negative bacteria, and its synergy with antibiotics determined using checkerboard assays followed by isobologram analysis. WH was also tested for its ability to suppress staphylococcal pathogenesis, which is the cause of a myriad of resistant infections. Here we show that WH inhibits the growth of all bacteria tested, with variable efficacy levels. The most WH-sensitive bacteria tested were Staphylococcus epidermidis, Staphylococcus aureus, Enterococcus faecium and Enterococcus faecalis, followed by Acinetobacter baumannii, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Streptococcus agalactiae and Streptococcus pneumoniae. Furthermore, WH was shown on S. aureus to be synergistic to linezolid and chloramphenicol and cumulative to vancomycin and amikacin. The effect of WH was tested on staphylococcal pathogenesis and shown here to inhibit biofilm formation (tested on S. epidermidis) and toxin production (tested on S. aureus Enterotoxin A (SEA)). Toxin inhibition was also evident in the presence of subinhibitory concentrations of ciprofloxacin that induces pathogenesis. Put together, our study indicates that WH is very effective in inhibiting the growth of multiple types of bacteria, is synergistic to antibiotics, and is also effective against staphylococcal pathogenesis, often the cause of persistent infections. Our study thus suggests the benefits of using WH to combat various types of bacterial infections, especially those that involve resistant persistent bacterial pathogens.

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Chan, Wai Ting, Inma Moreno-Córdoba, Chew Chieng Yeo, and Manuel Espinosa. "Toxin-Antitoxin Genes of the Gram-Positive Pathogen Streptococcus pneumoniae: So Few and Yet So Many." Microbiology and Molecular Biology Reviews 76, no. 4 (November 29, 2012): 773–91. http://dx.doi.org/10.1128/mmbr.00030-12.

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SUMMARYPneumococcal infections cause up to 2 million deaths annually and raise a large economic burden and thus constitute an important threat to mankind. Because of the increase in the antibiotic resistance ofStreptococcus pneumoniaeclinical isolates, there is an urgent need to find new antimicrobial approaches to triumph over pneumococcal infections. Toxin-antitoxin (TA) systems (TAS), which are present in most living bacteria but not in eukaryotes, have been proposed as an effective strategy to combat bacterial infections. Type II TAS comprise a stable toxin and a labile antitoxin that form an innocuous TA complex under normal conditions. Under stress conditions, TA synthesis will be triggered, resulting in the degradation of the labile antitoxin and the release of the toxin protein, which would poison the host cells. The three functional chromosomal TAS fromS. pneumoniaethat have been studied as well as their molecular characteristics are discussed in detail in this review. Furthermore, a meticulous bioinformatics search has been performed for 48 pneumococcal genomes that are found in public databases, and more putative TAS, homologous to well-characterized ones, have been revealed. Strikingly, several unusual putative TAS, in terms of components and genetic organizations previously not envisaged, have been discovered and are further discussed. Previously, we reported a novel finding in which a unique pneumococcal DNA signature, the BOX element, affected the regulation of the pneumococcalyefM-yoeBTAS. This BOX element has also been found in some of the other pneumococcal TAS. In this review, we also discuss possible relationships between some of the pneumococcal TAS with pathogenicity, competence, biofilm formation, persistence, and an interesting phenomenon called bistability.

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Zafar, M. Ammar, Yang Wang, Shigeto Hamaguchi, and Jeffrey N. Weiser. "Host-to-Host Transmission of Streptococcus pneumoniae Is Driven by Its Inflammatory Toxin, Pneumolysin." Cell Host & Microbe 21, no. 1 (January 2017): 73–83. http://dx.doi.org/10.1016/j.chom.2016.12.005.

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Duane, P. G., J. B. Rubins, H. R. Weisel, and E. N. Janoff. "Identification of hydrogen peroxide as a Streptococcus pneumoniae toxin for rat alveolar epithelial cells." Infection and Immunity 61, no. 10 (1993): 4392–97. http://dx.doi.org/10.1128/iai.61.10.4392-4397.1993.

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Al-Qaysi, Safaa A. S., Halah Al-Haideri, Zaid Akram Thabit, Wijdan Hameed Abd Al-Razzaq Al-Kubaisy, and Jamal Abd Al-Rahman Ibrahim. "Production, Characterization, and Antimicrobial Activity of Mycocin Produced byDebaryomyces hanseniiDSMZ70238." International Journal of Microbiology 2017 (2017): 1–9. http://dx.doi.org/10.1155/2017/2605382.

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The present study was conducted to estimate the antimicrobial activity and the potential biological control of the killer toxin produced byD. hanseniiDSMZ70238 against several pathogenic microorganisms. In this study, the effects of NaCl, pH, and temperature, killer toxin production, and antimicrobial activity were studied. The results showed that the optimum inhibitory effect of killer toxin was at 8% NaCl, and the diameters of clear zones were 20, 22, 22, 21, 14, and 13 mm forStaphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Streptococcus pyogenes, Candida albicans,andCandida neoformans, respectively. The largest inhibition zones were observed at pH 4.5 with inhibition zone of 16, 18, 17, 18, 11, and 12 mm for the same microorganisms. The results also showed that 25°C is the optimal temperature for toxin killing activity against all targeted microorganisms. In addition, the activity of killer toxin significantly inhibited the growth of fungal mycelia for all target pathogenic fungi and the percentages of inhibition were 47.77, 48.88, 52.22, and 61.11% forTrichophyton rubrum, Alternaria alternata, Trichophyton concentricum,andCurvularia lunata, respectively. The results showed the highest growth rate ofD. hanseniiDSMZ70238 under condition of 8% NaCl concentration, pH 4.5, and 25°C for 72 h.

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Ye, Chu, Lin, Yang, and Ma. "First-In-Class Inhibitors Targeting the Interaction between Bacterial RNA Polymerase and Sigma Initiation Factor Affect the Viability and Toxin Release of Streptococcus pneumoniae." Molecules 24, no. 16 (August 9, 2019): 2902. http://dx.doi.org/10.3390/molecules24162902.

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Novel antimicrobial classes are in desperate need for clinical management of infections caused by increasingly prevalent multi-drug resistant pathogens. The protein-protein interaction between bacterial RNA polymerase (RNAP) and the housekeeping sigma initiation factor is essential to transcription and bacterial viability. It also presents a potential target for antimicrobial discovery, for which a hit compound (C3) was previously identified from a pharmacophore model-based in silico screen. In this study, the hit compound was experimentally assessed with some rationally designed derivatives for the antimicrobial activities, in particular against Streptococcus pneumoniae and other pathogens. One compound, C3-005, shows dramatically improved activity against pneumococci compared to C3. C3-005 also attenuates S. pneumoniae toxin production more strongly than existing classes of antibiotics tested. Here we demonstrate a newly validated antimicrobial agent to address an overlooked target in the hit-to-lead process, which may pave the way for further antimicrobial development.

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Zainel, Abdulwahed, Hana Mitchell, and Manish Sadarangani. "Bacterial Meningitis in Children: Neurological Complications, Associated Risk Factors, and Prevention." Microorganisms 9, no. 3 (March 5, 2021): 535. http://dx.doi.org/10.3390/microorganisms9030535.

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Bacterial meningitis is a devastating infection, with a case fatality rate of up to 30% and 50% of survivors developing neurological complications. These include short-term complications such as focal neurological deficit and subdural effusion, and long-term complications such as hearing loss, seizures, cognitive impairment and hydrocephalus. Complications develop due to bacterial toxin release and the host immune response, which lead to neuronal damage. Factors associated with increased risk of developing neurological complications include young age, delayed presentation and Streptococcus pneumoniae as an etiologic agent. Vaccination is the primary method of preventing bacterial meningitis and therefore its complications. There are three vaccine preventable causes: Haemophilus influenzae type b (Hib), S. pneumoniae, and Neisseria meningitidis. Starting antibiotics without delay is also critical to reduce the risk of neurological complications. Additionally, early adjuvant corticosteroid use in Hib meningitis reduces the risk of hearing loss and severe neurological complications.

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Jansen, W. T. M., M. Bolm, R. Balling, G. S. Chhatwal, and R. Schnabel. "Hydrogen Peroxide-Mediated Killing of Caenorhabditis elegans by Streptococcus pyogenes." Infection and Immunity 70, no. 9 (September 2002): 5202–7. http://dx.doi.org/10.1128/iai.70.9.5202-5207.2002.

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ABSTRACT Caenorhabditis elegans is currently introduced as a new, facile, and cheap model organism to study the pathogenesis of gram-negative bacteria such as Pseudomonas aeruginosa and Salmonella enterica serovar Typhimurium. The mechanisms of killing involve either diffusible exotoxins or infection-like processes. Recently, it was shown that also some gram-positive bacteria kill C. elegans, although the precise mechanisms of killing remained open. We examined C. elegans as a pathogenesis model for the gram-positive bacterium Streptococcus pyogenes, a major human pathogen capable of causing a wide spectrum of diseases. We demonstrate that S. pyogenes kills C. elegans, both on solid and in liquid medium. Unlike P. aeruginosa and S. enterica serovar Typhimurium, the killing by S. pyogenes is solely mediated by hydrogen peroxide. Killing required live streptococci; the killing capacity depends on the amount of hydrogen peroxide produced, and killing can be inhibited by catalase. Major exotoxins of S. pyogenes are not involved in the killing process as confirmed by using specific toxin inhibitors and knockout mutants. Moreover, no accumulation of S. pyogenes in C. elegans is observed, which excludes the involvement of infection-like processes. Preliminary results show that S. pneumoniae can also kill C. elegans by hydrogen peroxide production. Hydrogen peroxide-mediated killing might represent a common mechanism by which gram-positive, catalase-negative pathogens kill C. elegans.

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Brumshagen, Christina, Regina Maus, Andrea Bischof, Bianca Ueberberg, Jennifer Bohling, John J. Osterholzer, Abiodun D. Ogunniyi, James C. Paton, Tobias Welte, and Ulrich A. Maus. "FMS-Like Tyrosine Kinase 3 Ligand Treatment of Mice Aggravates Acute Lung Injury in Response to Streptococcus pneumoniae: Role of Pneumolysin." Infection and Immunity 80, no. 12 (September 24, 2012): 4281–90. http://dx.doi.org/10.1128/iai.00854-12.

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ABSTRACTFMS-like tyrosine kinase-3 ligand (Flt3L) is a dendritic cell (DC) growth and differentiation factor with potential in antitumor therapies and antibacterial immunization strategies. However, the effect of systemic Flt3L treatment on lung-protective immunity against bacterial infection is incompletely defined. Here, we examined the impact of deficient (in Flt3L knockout [KO] mice), normal (in wild-type [WT] mice), or increased Flt3L availability (in WT mice pretreated with Flt3L for 3, 5, or 7 days) on lung DC subset profiles and lung-protective immunity against the major lung-tropic pathogen,Streptococcus pneumoniae. Although in Flt3L-deficient mice the numbers of DCs positive for CD11b (CD11bposDCs) and for CD103 (CD103posDCs) were diminished, lung permeability, a marker of injury, was unaltered in response toS. pneumoniae. In contrast, WT mice pretreated with Flt3L particularly responded with increased numbers of CD11bposDCs and with less pronounced numbers of CD103posDCs and impaired bacterial clearance and with increased lung permeability followingS. pneumoniae challenge. Notably, infection of Flt3L-pretreated mice withS. pneumoniaelacking the pore-forming toxin, pneumolysin (PLY), resulted in substantially less lung CD11bposDCs activation and reduced lung permeability. Collectively, this study establishes that Flt3L treatment enhances the accumulation of proinflammatory activated lung CD11bposDCs which contribute to acute lung injury in response to PLY released byS. pneumoniae.

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Iliev, A. I., J. R. Djannatian, R. Nau, T. J. Mitchell, and F. S. Wouters. "Cholesterol-dependent actin remodeling via RhoA and Rac1 activation by the Streptococcus pneumoniae toxin pneumolysin." Proceedings of the National Academy of Sciences 104, no. 8 (February 14, 2007): 2897–902. http://dx.doi.org/10.1073/pnas.0608213104.

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Kim, Do-Hee, Sung-Min Kang, Sung Jean Park, Chenglong Jin, Hye-Jin Yoon, and Bong-Jin Lee. "Functional insights into the Streptococcus pneumoniae HicBA toxin–antitoxin system based on a structural study." Nucleic Acids Research 46, no. 12 (June 6, 2018): 6371–86. http://dx.doi.org/10.1093/nar/gky469.

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Journal articles on the topic 'Streptococcus pneumoniae toxins'

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