The molecular mechanism of pneumolysin, a virulence factor from Streptococcus pneumoniae 1 1Edited by J. Thornton

Rossjohn, Jamie; Gilbert, R.J.C.; Crane, Dennis; Morgan, Peter J.; Mitchell, Tim; Rowe, Arthur J.; Andrew, Peter W.; Paton, James C.; Tweten, Rodney K.; Parker, Michael W.

doi:10.1006/jmbi.1998.2167

Cited by 107 publications

(95 citation statements)

References 43 publications

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“…Thus, although further mutational analyses are required to pinpoint the exact sLeXbinding site, our data suggest that the site predicted by the PFObased model is the more accurate reflection of the true situation in native Ply. Previous studies have proposed that the conserved undecapeptide region of Ply, and W433 in particular, is critically important for the toxin's capacity to bind membrane cholesterol (41). However, our data now suggest that this region may be more important for the glycan interactions that precede cholesteroldependent toxin oligomerization and membrane insertion.…”

Section: Discussioncontrasting

confidence: 49%

The cholesterol-dependent cytolysins pneumolysin and streptolysin O require binding to red blood cell glycans for hemolytic activity

Shewell

Harvey

Higgins

et al. 2014

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

105

113

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The cholesterol-dependent cytolysin (CDC) pneumolysin (Ply) is a key virulence factor of Streptococcus pneumoniae. Membrane cholesterol is required for the cytolytic activity of this toxin, but it is not clear whether cholesterol is the only cellular receptor. Analysis of Ply binding to a glycan microarray revealed that Ply has lectin activity and binds glycans, including the Lewis histoblood group antigens. Surface plasmon resonance analysis showed that Ply has the highest affinity for the sialyl LewisX (sLeX) structure, with a K d of 1.88 × 10 −5 M. Ply hemolytic activity against human RBCs showed dose-dependent inhibition by sLeX. Flow cytometric analysis and Western blots showed that blocking binding of Ply to the sLeX glycolipid on RBCs prevents deposition of the toxin in the membrane. The lectin domain responsible for sLeX binding is in domain 4 of Ply, which contains candidate carbohydrate-binding sites. Mutagenesis of these predicted carbohydrate-binding residues of Ply resulted in a decrease in hemolytic activity and a reduced affinity for sLeX. This study reveals that this archetypal CDC requires interaction with the sLeX glycolipid cellular receptor as an essential step before membrane insertion. A similar analysis conducted on streptolysin O from Streptococcus pyogenes revealed that this CDC also has glycan-binding properties and that hemolytic activity against RBCs can be blocked with the glycan lacto-N-neotetraose by inhibiting binding to the cell surface. Together, these data support the emerging paradigm shift that pore-forming toxins, including CDCs, have cellular receptors other than cholesterol that define target cell tropism.S treptococcus pneumoniae is a leading cause of morbidity and mortality worldwide. This bacterial pathogen is responsible for a range of diseases, including pneumonia, meningitis, septicemia, and otitis media. One of the major virulence factors of S. pneumoniae is the multifunctional pore-forming toxin pneumolysin (Ply). Ply is produced by virtually all clinical isolates of S. pneumoniae and is a member of the cholesterol-dependent cytolysin (CDC) family of toxins (1). The key feature of the CDCs, which are expressed by a number of pathogenic Grampositive bacteria, is the ability to form pores in cholesterolcontaining cell membranes. The pore-forming mechanism of the CDCs is a multistep process that involves recognition and binding to the cholesterol-containing membrane by domain 4 of the toxin, oligomerization of ∼34-50 soluble monomers on the target cell membrane to form a large prepore complex (2), and penetration of the prepore structure into the membrane to become a transmembrane β-barrel pore (3-5).The cytolytic mechanism of the CDCs depends on the presence of cholesterol in the target cell membrane; hence, it was thought that cholesterol served as the cellular receptor for these toxins. The first suggestion of this cholesterol serving as the receptor occurred in the 1970s, when it was found that preincubation of the CDC of Streptococcus pyogenes, streptolysin O (SL...

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Section: Discussioncontrasting

confidence: 49%

The cholesterol-dependent cytolysins pneumolysin and streptolysin O require binding to red blood cell glycans for hemolytic activity

Shewell

Harvey

Higgins

et al. 2014

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

105

113

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“…6 Similarly, SLO might have the potential to confer virulence without the assistance of SPN, presumably because of its ability to destroy host cell membranes and cause cell injuries. Many SLO-like cholesterol-dependent cytolysins made by other streptococcal pathogens (eg, pneumolysin in Streptococcus pneumoniae and suilysin in Streptococcus suis) are known virulence factors, 35,36 but they are not coupled with NADase. In summary, our mouse virulence data confirmed the functional association between SPN and SLO.…”

Section: Discussionmentioning

confidence: 99%

Contribution of Secreted NADase and Streptolysin O to the Pathogenesis of Epidemic Serotype M1 Streptococcus pyogenes Infections

Zhu

Olsen

Lee

et al. 2017

The American Journal of Pathology

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Streptococcus pyogenes secretes many toxins that facilitate human colonization, invasion, and dissemination. NADase (SPN) and streptolysin O (SLO) are two toxins that play important roles in pathogenesis. We previously showed that increased production of SPN and SLO in epidemic serotype M1 and M89 S. pyogenes strains is associated with rapid intercontinental spread and enhanced virulence. The biological functions of SPN and SLO have been extensively studied using eukaryotic cell lines, but the relative contribution of each of these two toxins to pathogenesis of epidemic M1 or M89 strains remains unexplored. Herein, using a genetically representative epidemic M1 strain and a panel of isogenic mutant derivative strains, we evaluated the relative contributions of SPN and SLO toxins to virulence in mouse models of necrotizing myositis, bacteremia, and skin and soft tissue infection. We found that isogenic mutants lacking SPN, SLO, and both toxins are equally impaired in ability to cause necrotizing myositis. In addition, mutants lacking either SPN or SLO are significantly attenuated in the bacteremia and soft tissue infection models, and the mutant strain lacking production of both toxins is further attenuated. The mutant strain lacking both SPN and SLO production is severely attenuated in ability to resist killing by human polymorphonuclear leukocytes. We conclude that both SPN and SLO contribute significantly to S. pyogenes pathogenesis in these virulence assays. (Am J Pathol 2017, 187: 605e613; http://dx.doi.org/10.1016/j.ajpath.2016.11.003) Streptococcus pyogenes (alias group A Streptococcus) is a major bacterial pathogen causing human morbidity and mortality globally. Streptococcus pyogenes produces many virulence factors that facilitate transmission, colonization, invasion, and dissemination.1 NADase (SPN) and streptolysin O (SLO) are two potent cytotoxins secreted by S. pyogenes, and multiple roles in virulence have been attributed to each protein. SPN is actively translocated into the host cells, resulting in cell injury and death via depletion of host cell NAD þ . 2e4 SLO is a cholesteroldependent cytolysin that forms pores in host cell membranes. SPN and SLO inhibit phagocytosis, 3 inhibit maturation of autophagosomes, 5,6 impair neutrophil oxidative burst, 7 and prevent the killing of S. pyogenes by a variety of host immune cells. 3,5e8 SPN and SLO are interconnected in many ways. Several lines of evidence suggest that the SPN and SLO proteins interact physically.4,9e11 Moreover, SPN and SLO toxins are functionally related. For example, translocation of SPN into host cells requires SLO.2 In addition, binding of SPN to the host cell membrane promotes SLOmediated pore formation.

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“…Of great interest, a recent report demonstrated that pneumolysin, known as a major toxic component of S. pneumoniae, signals via TLR4 (22). Pneumolysin gets released upon lysis of pneumococci during multiplication of bacteria and has many biological activities like induction of cytokines and cytotoxicity (41)(42)(43). Malley et al (22) used a model of i.n.…”

Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor 2 Plays a Role in the Early Inflammatory Response to Murine Pneumococcal Pneumonia but Does Not Contribute to Antibacterial Defense

Knapp¹,

Wieland²,

Veer

et al. 2004

The Journal of Immunology

244

243

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Toll-like receptors (TLR) are crucial pattern recognition receptors in innate immunity. The importance of TLR2 in host defense against Gram-positive bacteria has been suggested by the fact that this receptor recognizes major Gram-positive cell wall components, such as peptidoglycan and lipoteichoic acid. To determine the role of TLR2 in pulmonary Gram-positive infection, we first established that TLR2 is indispensable for alveolar macrophage responsiveness toward Streptococcus pneumoniae. Nonetheless, TLR2 gene-deficient mice intranasally inoculated with S. pneumoniae at doses varying from nonlethal (with complete clearance of the infection) to lethal displayed only a modestly reduced inflammatory response in their lungs and an unaltered antibacterial defense when compared with normal wild-type mice. These data suggest that TLR2 plays a limited role in the innate immune response to pneumococcal pneumonia, and that additional pattern recognition receptors likely are involved in host defense against this common respiratory pathogen.

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The molecular mechanism of pneumolysin, a virulence factor from Streptococcus pneumoniae 1 1Edited by J. Thornton

Cited by 107 publications

References 43 publications

The cholesterol-dependent cytolysins pneumolysin and streptolysin O require binding to red blood cell glycans for hemolytic activity

The cholesterol-dependent cytolysins pneumolysin and streptolysin O require binding to red blood cell glycans for hemolytic activity

Contribution of Secreted NADase and Streptolysin O to the Pathogenesis of Epidemic Serotype M1 Streptococcus pyogenes Infections

Toll-Like Receptor 2 Plays a Role in the Early Inflammatory Response to Murine Pneumococcal Pneumonia but Does Not Contribute to Antibacterial Defense

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