ArticleProceedings of the National Academy of Sciences of the United States of America2014
The cholesterol-dependent cytolysins pneumolysin and streptolysin O require binding to red blood cell glycans for hemolytic activity.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 74 papers.
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Who cites it
74 citing papers in PubMed, 114 citations in OpenAlex.
- Extracellular Vesicle-Bound Bacterial Toxin Pneumolysin Triggers Membrane Engagement and Damage Beyond Canonical Pore Formation.Journal of extracellular vesicles · 2026Article
- LC3 forms functional nanoclusters on autophagosomes.EMBO reports · 2026Article
- Bioengineered Extracellular Vesicles Mitigate Neuroinflammation by Neutralizing Pneumolysin and Delaying Disease Onset in Experimental Pneumococcal Meningitis.Journal of extracellular vesicles · 2026Article
- A fully human streptolysin O-neutralizing monoclonal antibody improves survival in a murine model of group A streptococcus necrotizing soft tissue infection.Antimicrobial agents and chemotherapy · 2026Article
- Heparin-binding enhances extracellular listeriolysin O activity, overcoming cholesterol inhibition and pH dependence.Journal of bacteriology · 2026Article
- Pore Formation by Pore Forming Proteins in Lipid Membranes: Structural Insights Through Cryo-EM.The Journal of membrane biology · 2025Review
- Insights into the Protein-Lipid Interaction of Perivitellin-2, an Unusual Snail Pore-Forming Toxin.Toxins · 2025Article
- Article
- Clinical Snapshot of Group A Streptococcal Isolates from an Australian Tertiary Hospital.Pathogens (Basel, Switzerland) · 2024Article
- Streptolysin S is required for Streptococcus pyogenes nasopharyngeal and skin infection in HLA-transgenic mice.PLoS pathogens · 2024Article
- Development and characterization of a hemolysis inhibition assay to determine functionality of anti-Streptolysin O antibodies in human sera.Journal of immunological methods · 2024Article
- Characterization of tigurilysin, a novel human CD59-specific cholesterol-dependent cytolysin, reveals a role for host specificity in augmenting toxin activity.Microbiology (Reading, England) · 2023Article
- Characterization of Tigurilysin, a Novel Human CD59-Specific Cholesterol-Dependent Cytolysin, Reveals a Role for Host Specificity in Augmenting Toxin Activity.bioRxiv : the preprint server for biology · 2023Article
- Article
- Structural basis underlying the synergism of NADase and SLO during group A Streptococcus infection.Communications biology · 2023Article
- Article
- V. cholerae MakA is a cholesterol-binding pore-forming toxin that induces non-canonical autophagy.The Journal of cell biology · 2022Article
- Cholesterol-dependent cytolysins: The outstanding questions.IUBMB life · 2022Review
- Single Point Mutation and Its Role in Specific Pathogenicity to Reveal the Mechanism of Related Protein Families.Microbiology spectrum · 2022Article
- The exploitation of human glycans by Group A Streptococcus.FEMS microbiology reviews · 2022Article
14 more citing papers are in PubMed but not listed here.
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Authors and funding
14 authors at 4 institutions in 2 countries.
Funding
Abstract
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 histo-blood 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.
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