Group A Streptococcus (GAS) is one of the most significant global pathogens, causing many common symptoms such as pharyngitis, cellulitis, and impetigo. It is also responsible for more severe diseases such as rheumatic fever, necrotizing fasciitis, and toxic shock syndrome. A landmark feature of GAS is its ability to produce a powerful toxin known as Streptolysin S (SLS). It has been widely held that SLS acts as a major contributing factor during invasive Group A Streptococcus infection through rapid membrane-based destruction of cells and tissues during the infection process. However, recent studies by our laboratory and others suggest that SLS may also play a more complex role in disease at physiologically relevant levels, including its ability to precisely target and inactivate host proteins. SLS has been identified to belong to a conserved family of small, ribosomally produced bacteriocin-like peptides that are structurally distinguished by the posttranslational installation of heterocycles on specific amino acid residues. Many of these related bacteriocins have defined cellular targets and have not been shown to function as general lytic agents of cellular membranes. Indeed, our recent work has shown that the mechanism by which SLS exerts its beta-hemolytic activity is via targeted disruption of the Band 3 anion transporter. We show for the first time, using high-resolution live cell imaging, that SLS 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 hemolytic activity of streptolysin S, and reduced pathology in an in vivo skin model of GAS infection.
Findings from our study will have important implications for developing targeted therapeutics against Group A Streptococcus as well as revealing novel strategies to treat and prevent Streptococcal disease.