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

    Author(s)
    Shewell, Lucy K
    Harvey, Richard M
    Higgins, Melanie A
    Day, Christopher J
    Hartley-Tassell, Lauren E
    Chen, Austen Y
    Gillen, Christine M
    James, David BA
    Alonzo, Francis
    Torres, Victor J
    Walker, Mark J
    Paton, Adrienne W
    Paton, James C
    Jennings, Michael P
    Griffith University Author(s)
    Jennings, Michael P.
    Day, Christopher J.
    Year published
    2014
    Metadata
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    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 Kd of 1.88 ! 10!5 M. Ply hemolytic activity against human RBCs showed dose-dependent inhibition ...
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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 histo- blood group antigens. Surface plasmon resonance analysis showed that Ply has the highest affinity for the sialyl LewisX (sLeX) structure, with a Kd 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 car- bohydrate-binding sites. Mutagenesis of these predicted carbohy- drate-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 cellu- lar 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 proper- ties 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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    Journal Title
    Proceedings of the National Academy of Sciences of the United States of America
    Volume
    111
    Issue
    49
    DOI
    https://doi.org/10.1073/pnas.1412703111
    Subject
    Infectious agents
    Publication URI
    http://hdl.handle.net/10072/68906
    Collection
    • Journal articles

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