Pneumolysin plays a key role at the initial step of establishing pneumococcal nasal colonization

Hotomi, Muneki; Yuasa, Jun; Briles, David E.; Yamanaka, Noboru

doi:10.1007/s12223-016-0445-z

Cited by 26 publications

(19 citation statements)

References 46 publications

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“…PLY alone is capable of causing the salient histological features of lobar pneumonia in rat lungs [5], and ply-deficient mutants are attenuated in murine models of infection with alleviated induction of pneumocyte injury and the inflammatory response [6,7]. In addition, a novel role of PLY in enabling nasopharyngeal colonization by pneumococcus has been demonstrated recently [8]. These findings indicate that PLY is an important candidate as a target for antivirulence drug development.…”

Section: Introductionmentioning

confidence: 94%

Epigallocatechin gallate inhibits Streptococcus pneumoniae virulence by simultaneously targeting pneumolysin and sortase A

Meng

Teng

et al. 2017

J Cellular Molecular Medi

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Streptococcus pneumoniae (pneumococcus), the causative agent of several human diseases, possesses numerous virulence factors associated with pneumococcal infection and pathogenesis. Pneumolysin (PLY), an important virulence factor, is a member of the cholesterol‐dependent cytolysin family and has cytolytic activity. Sortase A (SrtA), another crucial pneumococcal virulence determinate, contributes greatly to the anchoring of many virulence‐associated surface proteins to the cell wall. In this study, epigallocatechin gallate (EGCG), a natural compound with little known antipneumococcal activity, was shown to directly inhibit PLY‐mediated haemolysis and cytolysis by blocking the oligomerization of PLY and simultaneously reduce the peptidase activity of SrtA. The biofilm formation, production of neuraminidase A (NanA, the pneumococcal surface protein anchored by SrtA), and bacterial adhesion to human epithelial cells (Hep2) were inhibited effectively when S. pneumoniae D39 was cocultured with EGCG. The results from molecular dynamics simulations and mutational analysis confirmed the interaction of EGCG with PLY and SrtA, and EGCG binds to Glu277, Tyr358, and Arg359 in PLY and Thr169, Lys171, and Phe239 in SrtA. In vivo studies further demonstrated that EGCG protected mice against S. pneumoniae pneumonia. Our results imply that EGCG is an effective inhibitor of both PLY and SrtA and that an antivirulence strategy that directly targets PLY and SrtA using EGCG is a promising therapeutic option for S. pneumoniae pneumonia.

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Section: Introductionmentioning

confidence: 94%

Epigallocatechin gallate inhibits Streptococcus pneumoniae virulence by simultaneously targeting pneumolysin and sortase A

Meng

Teng

et al. 2017

J Cellular Molecular Medi

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“…vaginalis , despite considerable genetic diversity in this species [ 28 , 47 ]. Second, other CDC’s, such as pneumolysin and listeriolysin, play critical roles in colonization and pathogenesis [ 48 , 49 ]. G .…”

Section: Discussionmentioning

confidence: 99%

Association between statin use, the vaginal microbiome, and Gardnerella vaginalis vaginolysin-mediated cytotoxicity

Abdelmaksoud¹,

Girerd²,

Garcia³

et al. 2017

PLoS ONE

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BackgroundBacterial vaginosis (BV) is the leading dysbiosis of the vaginal microbiome. The pathways leading towards the development of BV are not well understood. Gardnerella vaginalis is frequently associated with BV. G. vaginalis produces the cholesterol-dependent cytolysin (CDC), vaginolysin, which can lyse a variety of human cells and is thought to play a role in pathogenesis. Because membrane cholesterol is required for vaginolysin to function, and because HMG-CoA reductase inhibitors (statins) affect not only serum levels of cholesterol but membrane levels as well, we hypothesized that statins might affect the vaginal microbiome.MethodsTo investigate the relationship between use of the statins and the vaginal microbiome, we analyzed 16S rRNA gene taxonomic surveys performed on vaginal samples from 133 women who participated in the Vaginal Human Microbiome Project and who were taking statins at the time of sampling, 152 women who reported high cholesterol levels but were not taking statins, and 316 women who did not report high cholesterol. To examine the effect of statins on the cytolytic effect of vaginolysin, the cholesterol-dependent cytolysin (CDC) produced by Gardnerella vaginalis, we assessed the effect of simvastatin pretreatment of VK2E6/E7 vaginal epithelial cells on vaginolysin-mediated cytotoxicity.ResultsThe mean proportion of G. vaginalis among women taking statins was significantly lower relative to women not using statins. Women using statins had higher mean proportions of Lactobacillus crispatus relative to women with normal cholesterol levels, and higher levels of Lactobacillus jensenii relative to women with high cholesterol but not taking statins. In vitro, vaginal epithelial cells pretreated with simvastatin were relatively resistant to vaginolysin and this effect was inhibited by cholesterol.ConclusionsIn this cross-sectional study, statin use was associated with reduced proportions of G. vaginalis and greater proportions of beneficial lactobacilli within the vaginal microbiome. The negative association between statin use and G. vaginalis may be related to inhibition of vaginolysin function.

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“…Together with various pneumococcal epithelial adhesins, as well as the polysaccharide capsule which, in addition to anti-phagocytic properties, enables attachment of the pathogen to airway mucus, 75 Ply contributes to early colonisation not only via interference with the beating and coordinated expulsive actions of the mucociliary escalator, but also by directly damaging respiratory epithelium. 76,77 Thereafter, the pneumococcus may be transiently controlled by innate host defences then eradicated following effective activation of both antibody-and cell-mediated host defences. 78,79 Alternatively, the pneumococcus may enter a quiescent phase, often concealed in biofilm.…”

Section: Role Of Pneumolysin In Evasion Of Host Defencesmentioning

confidence: 99%

Pneumolysin as a potential therapeutic target in severe pneumococcal disease

Feldman

2017

Journal of Infection

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Acute pulmonary and cardiac injury remain significant causes of morbidity and mortality in those afflicted with severe pneumococcal disease, with the risk for early mortality often persisting several years beyond clinical recovery. Although remaining to be firmly established in the clinical setting, a considerable body of evidence, mostly derived from murine models of experimental infection, has implicated the pneumococcal, cholesterol-binding, pore-forming toxin, pneumolysin (Ply), in the pathogenesis of lung and myocardial dysfunction. Topics covered in this review include the burden of pneumococcal disease, risk factors, virulence determinants of the pneumococcus, complications of severe disease, antibiotic and adjuvant therapies, as well as the structure of Ply and the role of the toxin in disease pathogenesis. Given the increasing recognition of the clinical potential of Ply-neutralisation strategies, the remaining sections of the review are focused on updates of the types, benefits and limitations of currently available therapies which may attenuate, directly and/or indirectly, the injurious actions of Ply. These include recently described experimental therapies such as various phytochemicals and lipids, and a second group of more conventional agents the members of which remain the subject of ongoing clinical evaluation. This latter group, which is covered more extensively, encompasses macrolides, statins, corticosteroids, and platelet-targeted therapies, particularly aspirin.

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Pneumolysin plays a key role at the initial step of establishing pneumococcal nasal colonization

Cited by 26 publications

References 46 publications

Epigallocatechin gallate inhibits Streptococcus pneumoniae virulence by simultaneously targeting pneumolysin and sortase A

Epigallocatechin gallate inhibits Streptococcus pneumoniae virulence by simultaneously targeting pneumolysin and sortase A

Association between statin use, the vaginal microbiome, and Gardnerella vaginalis vaginolysin-mediated cytotoxicity

Pneumolysin as a potential therapeutic target in severe pneumococcal disease

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