Pneumolysin Induces the Salient Histologic Features of Pneumococcal Infection in the Rat Lung <i>In Vivo</i>

Feldman, Charles; Munro, N. C.; Jeffery, P. K.; Mitchell, Tim; Andrew, Peter W.; Boulnois, Graham J.; Guerreiro, D.; Rohde, J. A. L.; Todd, Howard; Cole, Peter; Wilson, Roger H. L.

doi:10.1165/ajrcmb/5.5.416

Cited by 101 publications

(58 citation statements)

References 34 publications

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“…Ply-deficient strains of S. pneumoniae are attenuated in animal models of pneumonia and sepsis (13). In addition, purified toxin is sufficient to induce many of the features of pneumococcal lung disease, including neutrophil recruitment, just as it recapitulated the effect of whole S. pneumoniae in our experiments (39). Here, we demonstrate that Ply is necessary and sufficient for the pneumococcal contribution to synergistic epithelial activation, an effect that is independent of TLR4 (18).…”

Section: Discussionsupporting

confidence: 66%

Synergistic proinflammatory responses induced by polymicrobial colonization of epithelial surfaces

Ratner

Лысенко

Paul

et al. 2005

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

132

110

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The epithelial surfaces of the upper respiratory tract are continuously exposed to a wide variety of commensal microorganisms. In addition to acting as a physical barrier, epithelial cells respond to specific microbial products with the generation of signals, such as cytokines, that trigger inflammation. Because they are common components of the nasopharyngeal flora that share the potential to cause disease, we investigated the effects of Haemophilus influenzae and Streptococcus pneumoniae, alone and in combination, on human respiratory epithelial cells in culture and in a murine model of nasopharyngeal colonization. Exposure of A549 or Detroit 562 epithelial cells to both S. pneumoniae and H. influenzae led to a synergistic increase in production of IL-8, the major neutrophil chemokine in the airway, through an NF-B-dependent mechanism. Likewise, nasal cocolonization of mice caused a synergistic rise in local production of macrophage inflammatory protein 2 in nasal lavage fluid and subsequent recruitment of neutrophils. This synergistic effect depended on production of the pore-forming cytolytic toxin, pneumolysin, by S. pneumoniae and activation of host p38 mitogen-activated protein kinase. Although both H. influenzae and S. pneumoniae have ligands for Toll-like receptors (TLRs) TLR2 and TLR4, synergistic activation was TLR2-and TLR4-independent. Thus, epithelial surfaces are capable of amplifying proinflammatory responses during concurrent stimulation by multiple microbial species. These synergistic responses, demonstrated both in vitro and in vivo, may contribute to inflammation of heavily colonized mucosal barriers.Haemophilus influenzae ͉ inflammation ͉ nasopharyngeal colonization ͉ Streptococcus pneumoniae

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Section: Discussionsupporting

confidence: 66%

Synergistic proinflammatory responses induced by polymicrobial colonization of epithelial surfaces

Ratner

Лысенко

Paul

et al. 2005

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

132

110

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“…The importance of pneumolysin as a pneumococcal virulence factor was reported in several in vivo studies that showed reduced pathogenesis in mice infected with pneumolysin-deficient strains of S. pneumoniae compared with isogenic toxin-producing strains (27)(28)(29)(30). Furthermore, application of purified pneumolysin directly into the lungs of rats induced an acute inflammatory response similar to that observed during pneumococcal pneumonia (31).…”

mentioning

confidence: 73%

Human Lung Mast Cells Mediate Pneumococcal Cell Death in Response to Activation by Pneumolysin

Cruse

Fernandes

Salort

et al. 2010

The Journal of Immunology

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Mast cells are emerging as contributors to innate immunity. Mouse mast cells have a pivotal role in protection against bacterial infection, and human cord blood-derived mast cells reduce bacterial viability in culture. The objectives of this study were to determine whether human lung mast cells (HLMCs) might be protective against pneumococcal lung infection through direct antimicrobial activity. Tissue-derived HLMCs and the human mast cell lines HMC-1 and LAD2 were cocultured with wild-type and mutant pneumococci, and viability and functional assays were performed. Mast cells were also stimulated with purified pneumolysin. HLMCs killed wild-type serotype-2 (D39) pneumococci in coculture but had no effect on an isogenic pneumolysin-deficient (PLN-A) pneumococcus. D39 wild-type, but not PLN-A pneumococci, induced the release of leukotriene C4 from human mast cells in a dose-dependent manner, which was not accompanied by histamine release. Stimulation of mast cells with sublytic concentrations of purified pneumolysin replicated this effect. Furthermore, pneumolysin induced the release of the cathelicidin LL-37 from HLMCs, purified LL-37 reduced pneumococcal viability, and neutralizing Ab to LL-37 attenuated mast cell-dependent pneumococcal killing. In addition, at high concentrations, all pneumococcal strains tested reduced HLMC viability through a combination of pneumolysin and H2O2-dependent mechanisms. HLMCs exhibit direct antimicrobial activity to pneumococci through their activation by pneumolysin. This antimicrobial activity is mediated, in part, by the release of LL-37 from HLMCs. This suggests that mast cells provide an early warning system and potentially limit pneumococcal dissemination early in the course of invasive pulmonary pneumococcal disease.

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“…A leading candidate for such a protein-based vaccine is pneumolysin (PLY) 3 : it is an important virulence factor of S. pneumoniae (11,12), is highly conserved across all serotypes (13), is immunogenic in humans (14,15), and has shown protection in numerous animal models of infection (16 -18). However, PLY is a toxin that oligomerizes to form large pores in the membranes of target host cells (19).…”

mentioning

confidence: 99%

Structure-guided Antigen Engineering Yields Pneumolysin Mutants Suitable for Vaccination against Pneumococcal Disease

Oloo¹,

Yethon²,

Ochs

et al. 2011

Journal of Biological Chemistry

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Pneumolysin (PLY) is a cholesterol-binding, pore-forming protein toxin. It is an important virulence factor of Streptococcus pneumoniae and a key vaccine target against pneumococcal disease. We report a systematic structure-driven approach that solves a long-standing problem for vaccine development in this field: detoxification of PLY with retention of its antigenic integrity. Using three conformational restraint techniques, we rationally designed variants of PLY that lack hemolytic activity and yet induce neutralizing antibodies against the wild-type toxin. These results represent a key milestone toward a broad-spectrum protein-based pneumococcal vaccine and illustrate the value of structural knowledge in formulating effective strategies for antigen optimization.

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Pneumolysin Induces the Salient Histologic Features of Pneumococcal Infection in the Rat Lung In Vivo

Cited by 101 publications

References 34 publications

Synergistic proinflammatory responses induced by polymicrobial colonization of epithelial surfaces

Synergistic proinflammatory responses induced by polymicrobial colonization of epithelial surfaces

Human Lung Mast Cells Mediate Pneumococcal Cell Death in Response to Activation by Pneumolysin

Structure-guided Antigen Engineering Yields Pneumolysin Mutants Suitable for Vaccination against Pneumococcal Disease

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