Oral Presentation 20th Lancefield International Symposium on Streptococci and Streptococcal Diseases 2017

Identification of glycan receptors for streptococcal cholesterol dependent cytolysins.  (#120)

Michael Jennings 1 , Lucy K. Shewell 1 , Christopher J. Day 1 , Frederiek Reijneveld 1 , Sara L. Lawrence 2 , Michael W. Parker 2 , Christine M. Gillen 3 , Mark J. Walker 4 , Adrienne W. Paton 4 , James C. Paton 4
  1. Institute for Glycomics, Griffith University , GOLD COAST , QLD, Australia
  2. ACRF Rational Drug Discovery Centre, St. Vincent’s Institute of Medical Research, Fitzroy, Victoria, Australia
  3. School of Chemistry and Molecular Biosciences and the Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, QLD, Australia
  4. Research Centre for Infectious Diseases, School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA, Australia

The cholesterol-dependent cytolysins (CDCs) are key virulence factors expressed by many pathogenic Gram-positive bacteria, including the Streptococci. The defining feature of CDCs is the ability to form pores in cholesterol containing membranes. Because the CDC’s cytolytic mechanism depends on the presence of cholesterol in the target cell membrane it was believed that cholesterol served as the cellular receptor for these toxins. Using glycan microarrays and surface plasmon resonance we have identified high affinity interactions between all CDCs examined (n=7) and glycan structures. These include the streptococcal CDCs; pneumolysin (PLY), streptolysin O (SLO), intermedilysin (ILY), lectinolysin (LLY) and suilysin (SLY). Using human red blood cell hemolytic assays we demonstrate that the identified glycan targets can inhibit CDC mediated lysis when provide in solution as free oligosaccharides, thereby supporting their role as cellular receptors. ILY is unique among the CDCs in that it has previously been reported to use the glycoprotein CD59 as a receptor. We demonstrate that removal of the O-linked glycan from CD59 reduced binding of ILY to CD59, indicating that the glycan component of CD59 is key for receptor recognition. Lectin activity is a widespread feature among the CDCs. We propose that surface glycoproteins and/or glycolipids act as high-affinity cellular receptors for these toxins and dictate the tropism of these toxins.