title: Activation of band 3 mediates group A Streptococcus streptolysin S-based beta-haemolysis.
abstract: Streptococcus pyogenes, or group A Streptococcus (GAS), is a human bacterial pathogen that can manifest as a range of diseases from pharyngitis and impetigo to severe outcomes such as necrotizing fasciitis and toxic shock syndrome. GAS disease remains a global health burden with cases estimated at over 700 million annually and over half a million deaths due to severe infections(1). For over 100 years, a clinical hallmark of diagnosis has been the appearance of complete (beta) haemolysis when grown in the presence of blood. This activity is due to the production of a small peptide toxin by GAS known as streptolysin S. Although it has been widely held that streptolysin S exerts its lytic activity through membrane disruption, its exact mode of action has remained unknown. Here, we show, using high-resolution live cell imaging, that streptolysin S induces a dramatic osmotic change in red blood cells, leading to cell lysis. This osmotic change was characterized by the rapid influx of Cl(-) ions into the red blood cells through SLS-mediated disruption of the major erythrocyte anion exchange protein, band 3. Chemical inhibition of band 3 function significantly reduced the haemolytic activity of streptolysin S, and dramatically reduced the pathology in an in vivo skin model of GAS infection. These results provide key insights into the mechanism of streptolysin S-mediated haemolysis and have implications for the development of treatments against GAS.
authors: Department of Biological Sciences, University of Notre Dame, 100 Galvin Life Sciences Center, Notre Dame, Indiana 46556, USA.
authors: Dustin L
authors: DL
authors: Higashi
authors: Biology Department, Brooklyn College CUNY, New York 11210, USA.
authors: Nicolas
authors: N
authors: Biais
authors: W.M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, Indiana 46556, USA.
authors: Deborah L
authors: DL
authors: Donahue
authors: W.M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, Indiana 46556, USA.
authors: Jeffrey A
authors: JA
authors: Mayfield
authors: Indiana University School of Medicine, South Bend, Indiana 46617, USA.
authors: Charles R
authors: CR
authors: Tessier
authors: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
authors: Kevin
authors: K
authors: Rodriguez
authors: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
authors: Brandon L
authors: BL
authors: Ashfeld
authors: Department of Biological Sciences, University of Notre Dame, 100 Galvin Life Sciences Center, Notre Dame, Indiana 46556, USA.
authors: Jeffrey
authors: J
authors: Luchetti
authors: W.M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, Indiana 46556, USA.|Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
authors: Victoria A
authors: VA
authors: Ploplis
authors: W.M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, Indiana 46556, USA.|Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
authors: Francis J
authors: FJ
authors: Castellino
authors: Department of Biological Sciences, University of Notre Dame, 100 Galvin Life Sciences Center, Notre Dame, Indiana 46556, USA.|W.M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, Indiana 46556, USA.
authors: Shaun W
authors: SW
authors: Lee
mesh_terms: D000818:Animals; D001457:Anion Exchange Protein 1, Erythrocyte / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000187:drug effects; D006461:Hemolysis; D006801:Humans; D000069416:Intravital Microscopy; D051379:Mice; D012756:Sheep; D017192:Skin Diseases, Bacterial / Q000382:microbiology / Q000473:pathology; D013290:Streptococcal Infections / Q000382:microbiology / Q000473:pathology; D013297:Streptococcus pyogenes / Q000378:metabolism*; D013301:Streptolysins / Q000378:metabolism*
chemical_list: D001457:Anion Exchange Protein 1, Erythrocyte; D001426:Bacterial Proteins; D013301:Streptolysins; C026050:streptolysin S