Reduced Release of Pneumolysin by
            <i>Streptococcus pneumoniae</i>
            In Vitro and In Vivo after Treatment with Nonbacteriolytic Antibiotics in Comparison to Ceftriaxone

Spreer, Annette; Kerstan, Holger; Böttcher, Tobias; Gerber, Joachim; Siemer, Alexander; Zysk, Gregor; Mitchell, Tim; Eiffert, Helmut; Nau, Roland

doi:10.1128/aac.47.8.2649-2654.2003

Cited by 99 publications

(109 citation statements)

References 31 publications

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“…Although pneumolysin is located in the cytoplasm of S. pneumoniae, it is steadily released into the culture medium during growth in vitro, either through a basal level of autolysis (37) or via a yet to be characterized export mechanism (38). Free pneumolysin has also been detected in vivo during experimental infections (39). By binding C1q, pneumolysin, rather than inhibit the classical pathway, may actually increase complement activity, and how it is able to prevent complement deposition on S. pneumoniae is unclear at present.…”

Section: Discussionmentioning

confidence: 99%

Additive Inhibition of Complement Deposition by Pneumolysin and PspA Facilitates Streptococcus pneumoniae Septicemia

Yuste

Botto

Paton

et al. 2005

The Journal of Immunology

112

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Streptococcus pneumoniae is a common cause of septicemia in the immunocompetent host. To establish infection, S. pneumoniae has to overcome host innate immune responses, one component of which is the complement system. Using isogenic bacterial mutant strains and complement-deficient immune naive mice, we show that the S. pneumoniae virulence factor pneumolysin prevents complement deposition on S. pneumoniae, mainly through effects on the classical pathway. In addition, using a double pspA−/ply− mutant strain we demonstrate that pneumolysin and the S. pneumoniae surface protein PspA act in concert to affect both classical and alternative complement pathway activity. As a result, the virulence of the pspA−/ply− strain in models of both systemic and pulmonary infection is greatly attenuated in wild-type mice but not complement deficient mice. The sensitivity of the pspA−/ply− strain to complement was exploited to demonstrate that although early innate immunity to S. pneumoniae during pulmonary infection is partially complement-dependent, the main effect of complement is to prevent spread of S. pneumoniae from the lungs to the blood. These data suggest that inhibition of complement deposition on S. pneumoniae by pneumolysin and PspA is essential for S. pneumoniae to successfully cause septicemia. Targeting mechanisms of complement inhibition could be an effective therapeutic strategy for patients with septicemia due to S. pneumoniae or other bacterial pathogens.

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Section: Discussionmentioning

confidence: 99%

Additive Inhibition of Complement Deposition by Pneumolysin and PspA Facilitates Streptococcus pneumoniae Septicemia

Yuste

Botto

Paton

et al. 2005

The Journal of Immunology

112

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“…LAGROU et al [19] also reported that sub-MIC of erythromycin reduced the haemolytic activity of PLY by MRSP. SPREER et al [21] reported that in comparison to standard therapy with ceftriaxone, protein synthesis inhibitors such as rifampin and clindamycin reduced the release of PLY by S. pneumoniae in human cerebrospinal fluid during therapy of pneumococcal meningitis. The present results are in agreement with those studies.…”

Section: Discussionmentioning

confidence: 99%

“…Thereafter, pneumococci were lysed with protease inhibitor cocktails (Nacalai Tesque, Kyoto, Japan) with a sonicator (Ultrasonic Disruptor UD-201: Tomy Seiko, Tokyo, Japan) [20]. The western blot procedure for PLY was then performed as described previously [21]. Sample proteins (30 mg) of whole lysates were separated using SDS-PAGE (sodium dodecyl sulphate-polyacrylamide gel electrophoresis) and transferred onto nitrocellulose membranes.…”

Section: Western Blot Analysismentioning

confidence: 99%

Effects of macrolides on pneumolysin of macrolide-resistantStreptococcus pneumoniae

Fukuda¹,

Yanagihara²,

Higashiyama³

et al. 2006

Eur Respir J

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To clarify the discrepancy between increasing resistance and conservative clinical effects of macrolides on macrolide-resistant Streptococcus pneumoniae, the authors evaluated the effects of sub-minimum inhibitory concentrations of macrolides on pneumolysin.In vitro, S. pneumoniae was incubated with 1, 2 and 4 mg?mL -1 of clarithromycin (CLR) and azithromycin (AZM) for 8 h. Western blot analysis and haemolytic assay were performed to examine the production and activities of pneumolysin. In vivo, mice were infected with S. pneumoniae intra-nasally and treated with CLR (40 or 200 mg?kg -1 twice daily) or AZM (40 or 200 mg?kg -1 once daily) orally for 7 days. After 72 h post-infection, western blot analysis was performed to examine pneumolysin production in lungs. Survival rates were observed for 10 days.In vitro, every concentration of macrolide inhibited pneumolysin production more than the control. CLR (2 and 4 mg?mL ) improved the survival rates more than the control.The study results show that sub-minimum inhibitory concentrations of macrolides reduced pneumolysin. This might be related to the effectiveness of macrolides against pneumonia caused by high-level macrolide-resistant Streptococcus pneumoniae. Further investigations are necessary to evaluate the effects of macrolides on macrolide-resistant Streptococcus pneumoniae.

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“…In the present study, we investigated the effects of exposure of isolated human neutrophils to pneumolysin, at concentrations of 5-20 ng?mL -1 , in the presence and absence of the chemoattractant f-MLP on the release of MMP-8 and -9. Pneumolysin concentrations of up to 9 mg?mL -1 and 180 ng?mL -1 have been detected in pneumococcal culture fluids in vitro and in the cerebrospinal fluid of patients with pneumococcal meningitis, respectively [23,24]. N-formylated polypeptide chemoattractants are produced by the pneumococcus [25,26], and may act in concert with pneumolysin to augment the pro-inflammatory activities of neutrophils, as well as those of monocytes/ macrophages [4].…”

Section: Discussionmentioning

confidence: 99%

Pneumolysin induces release of matrix metalloproteinase-8 and -9 from human neutrophils

Cockeran¹,

Mitchell²,

Feldman³

2009

European Respiratory Journal

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The research question addressed in the current study was: does the pneumococcal pore-forming toxin, pneumolysin, mobilise matrix metalloproteinase (MMP) -8 and -9 from isolated human blood neutrophils at sublytic concentrations of 5, 10 and 20 ng?mL -1 ?MMPs were measured in the supernatants of unstimulated neutrophils and of cells exposed to pneumolysin and the chemoattractant N-formyl-L-methionyl-L-leucyl-L-phenylalanine (f-MLP; 0.1 mM), individually and in combination, using ELISA procedures, and alterations in cytosolic Ca 2+ concentrations were monitored using a fura-2 acetoxymethyl ester (fura-2/AM)-based spectrofluorimetric method. Treatment of neutrophils with pneumolysin alone caused dose-related release of both MMPs, whereas f-MLP caused modest increases; the combination of both activators was, however, most effective. Pneumolysin/f-MLP-activated release of the MMPs from the cells was paralleled by increases in cytosolic Ca 2+ .Exposure of human neutrophils to pneumolysin is accompanied by mobilisation of MMPs, which is potentiated by f-MLP. If operative in vivo, pneumolysin-mediated release of MMPs from neutrophils and other cell types may contribute to the pathogenesis of severe pneumococcal disease.

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Reduced Release of Pneumolysin by Streptococcus pneumoniae In Vitro and In Vivo after Treatment with Nonbacteriolytic Antibiotics in Comparison to Ceftriaxone

Cited by 99 publications

References 31 publications

Additive Inhibition of Complement Deposition by Pneumolysin and PspA Facilitates Streptococcus pneumoniae Septicemia

Additive Inhibition of Complement Deposition by Pneumolysin and PspA Facilitates Streptococcus pneumoniae Septicemia

Effects of macrolides on pneumolysin of macrolide-resistantStreptococcus pneumoniae

Pneumolysin induces release of matrix metalloproteinase-8 and -9 from human neutrophils

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