Activation of band 3 mediates group A Streptococcus streptolysin S-based beta-haemolysis
Dustin L Higashi1, Nicolas Biais2, Deborah L Donahue3
1Department of Biological Sciences, University of Notre Dame, 100 Galvin Life Sciences Center, Notre Dame, Indiana 46556, USA.
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.
Insights
Streptococcus pyogenes toxin streptolysin S causes red blood cell lysis by disrupting band 3 protein, leading to osmotic changes. Inhibiting band 3 reduces toxin activity and GAS infection pathology.
Area of Science:
- Microbiology
- Pathogen Research
- Molecular Biology
Background:
- Streptococcus pyogenes (group A Streptococcus, GAS) causes significant global health issues, including severe infections.
- GAS diagnosis often relies on observing beta-haemolysis, attributed to the streptolysin S (SLS) toxin.
- The precise mechanism of SLS-induced haemolysis has been unclear for over a century.
Purpose of the Study:
- To elucidate the molecular mechanism by which streptolysin S causes red blood cell lysis.
- To investigate the role of the erythrocyte anion exchange protein band 3 in SLS-mediated haemolysis.
- To assess the therapeutic potential of targeting band 3 in GAS infections.
Main Methods:
- High-resolution live cell imaging to observe red blood cell responses to SLS.
- Biochemical assays to analyze ion flux and protein interactions.
- In vivo studies using a mouse skin infection model.
Main Results:
- SLS induces rapid osmotic changes and lysis in red blood cells via Cl(-) influx.
- SLS disrupts the band 3 protein, a key anion exchanger in erythrocytes.
- Inhibition of band 3 function significantly reduces SLS haemolytic activity and in vivo GAS infection pathology.
Conclusions:
- Streptolysin S mediates haemolysis by disrupting the band 3 protein, causing osmotic imbalance.
- Targeting band 3 offers a potential therapeutic strategy against severe Streptococcus pyogenes infections.
- Understanding SLS's mechanism provides crucial insights for developing new anti-GAS treatments.
