The role of pneumolysin in mediating lung damage in a lethal pneumococcal pneumonia murine model

García-Suárez, María del Mar; Flórez, Noelia; Astudillo, Aurora; Vázquez, Fernando; Villaverde, Roberto; Fabrizio, Kevin; Pirofski, Liise Anne; Méndez, Francisco Javier

doi:10.1186/1465-9921-8-3

Cited by 59 publications

(61 citation statements)

References 50 publications

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“…Notwithstanding the previously documented direct, cytotoxic activities of Ply [8][9][10][11][12][13], the results of the current study are consistent with the existence of an additional potential mechanism of toxin-mediated acute adverse pulmonary and cardiac events, viz. platelet activation, which remains to be established in the clinical setting Nonetheless, these novel findings raise the important issue of the therapeutic potential of Ply-and platelet-directed therapies in the prevention or attenuation of pneumococcal CAP-related cardiac morbidity and mortality.…”

Section: As Shown Insupporting

confidence: 89%

“…PRP (10μl) in a final volume of 1ml Hanks' balanced salt solution (HBSS, indicator-free, 1.25 mM calcium, pH 7.4) was incubated for 5 min at 37°C after which one of the following was added: i) HBSS (control); ii) recombinant, endotoxin-free Ply (10,20,40,80 ng/ml); iii) Ply (40 ng/ml) in Ca 2+ -free HBSS; iv) inactive, recombinant delta6Ply (80 ng/ml); v) the conventional platelet activator, adenosine diphosphate (ADP, 100 mΜ) as a positive control system; or vi) platelet-activating factor (PAF, 400 nM) as an additional positive control system. The platelets were then incubated for a further 5 min period after which flow cytometric analyses were performed to determine CD62P expression.…”

Section: Methodsmentioning

confidence: 99%

“…Acute lung injury and multi-organ dysfunction syndrome, as well as acute cardiac events mostly occurring early in the course of CAP, have been identified as being significant contributors to mortality [1][2][3][4][5][6][7]. In the case of pneumococcal CAP, an increasing body of evidence, derived from both clinical and experimental studies, has implicated the major cytolytic, cholesterolbinding, pore-forming protein toxin, pneumolysin (Ply), in the pathogenesis of associated adverse pulmonary and cardiovascular events [8][9][10][11][12][13]. Although these harmful activities of Ply have been attributed to direct pulmonary and cardiac toxicity, it is noteworthy that Ply also possesses pro-inflammatory activities [14].…”

Section: Introductionmentioning

confidence: 99%

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Pneumolysin Mediates Platelet Activation In Vitro

Nel

Durandt

Mitchell

et al. 2016

Lung

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This study has explored the role of the pneumococcal toxin, pneumolysin (Ply), in activating human platelets. Following exposure to Ply [10-80 nanograms (ng)/ml], platelet activation and cytosolic Ca 2+ concentrations were measured flow cytometrically according to the level of expression of CD62P (P-selectin) and spectrofluorimetrically respectively. Exposure to Ply resulted in marked upregulation of expression of platelet CD62P, achieving statistical significance at concentrations of 40 ng/ml and higher (p<0.05), in the setting of increased influx of Ca 2+ . These potentially pro-thrombotic actions of Ply were attenuated by depletion of Ca 2+ from the extracellular medium, or by exposure of the cells to a pneumolysoid devoid of pore-forming activity. These findings are consistent with a mechanism of Plymediated platelet activation involving sub-lytic pore formation, Ca 2+ influx, and mobilization of CD62P-expressing α-granules, which, if operative in vivo, may contribute to the pathogenesis of associated acute lung and myocardial injury during invasive pneumococcal disease.

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Section: As Shown Insupporting

confidence: 89%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pneumolysin Mediates Platelet Activation In Vitro

Nel

Durandt

Mitchell

et al. 2016

Lung

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“…Furthermore, toxicity to alveolar epithelium disintegrates pulmonary architecture as well as weakens the alveolar-blood barrier, facilitating systemic bacterial dissemination. Although we have some understanding of bacterial virulence (4,5), the underlying molecular processes in mammalian host cells that mediate tissue damage are not fully understood, which limits the development of mitigation strategies.…”

mentioning

confidence: 99%

Streptococcus pneumoniaesecretes hydrogen peroxide leading to DNA damage and apoptosis in lung cells

Rai

Parrish

Tay

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

131

102

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Streptococcus pneumoniae is a leading cause of pneumonia and one of the most common causes of death globally. The impact of S. pneumoniae on host molecular processes that lead to detrimental pulmonary consequences is not fully understood. Here, we show that S. pneumoniae induces toxic DNA double-strand breaks (DSBs) in human alveolar epithelial cells, as indicated by ataxia telangiectasia mutated kinase (ATM)-dependent phosphorylation of histone H2AX and colocalization with p53-binding protein (53BP1). Furthermore, results show that DNA damage occurs in a bacterial contact-independent fashion and that Streptococcus pyruvate oxidase (SpxB), which enables synthesis of H 2 O 2 , plays a critical role in inducing DSBs. The extent of DNA damage correlates with the extent of apoptosis, and DNA damage precedes apoptosis, which is consistent with the time required for execution of apoptosis. Furthermore, addition of catalase, which neutralizes H 2 O 2 , greatly suppresses S. pneumoniae-induced DNA damage and apoptosis. Importantly, S. pneumoniae induces DSBs in the lungs of animals with acute pneumonia, and H 2 O 2 production by S. pneumoniae in vivo contributes to its genotoxicity and virulence. One of the major DSBs repair pathways is nonhomologous end joining for which Ku70/80 is essential for repair. We find that deficiency of Ku80 causes an increase in the levels of DSBs and apoptosis, underscoring the importance of DNA repair in preventing S. pneumoniaeinduced genotoxicity. Taken together, this study shows that S. pneumoniae-induced damage to the host cell genome exacerbates its toxicity and pathogenesis, making DNA repair a potentially important susceptibility factor in people who suffer from pneumonia.DNA damage | Streptococcus pneumoniae | hydrogen peroxide | γH2AX | Ku80

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“…KEYWORDS: Calcium, chemoattractants, matrix metalloproteinases, neutrophils, pneumolysin P neumolysin, a cholesterol-binding poreforming protein toxin, is a key virulence factor of the pneumococcus, which promotes dissemination of this microbial pathogen from the lungs to the vascular space via its proinflammatory and cytotoxic activities [1,2]. The pro-inflammatory activity of pneumolysin involves several distinct mechanisms.…”

mentioning

confidence: 99%

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

Cockeran¹,

Mitchell²,

Feldman³

2009

Eur Respir J

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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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The role of pneumolysin in mediating lung damage in a lethal pneumococcal pneumonia murine model

Abstract: Background: Intranasal inoculation of Streptococcus pneumoniae D39 serotype 2 causes fatal pneumonia in mice. The cytotoxic and inflammatory properties of pneumolysin (PLY) have been implicated in the pathogenesis of pneumococcal pneumonia.

Cited by 59 publications

References 50 publications

Pneumolysin Mediates Platelet Activation In Vitro

Pneumolysin Mediates Platelet Activation In Vitro

Streptococcus pneumoniaesecretes hydrogen peroxide leading to DNA damage and apoptosis in lung cells

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

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