Human Serum Albumin Binds Streptolysin O (SLO) Toxin Produced by Group A Streptococcus and Inhibits Its Cytotoxic and Hemolytic Effects

Abstract

The pathogenicity of group A <i>Streptococcus</i> (GAS) is mediated by direct bacterial invasivity and toxin-associated damage. Among the extracellular products, the exotoxin streptolysin O (SLO) is produced by almost all GAS strains. SLO is a pore forming toxin (PFT) hemolitically active and extremely toxic <i>in vivo</i>. Recent evidence suggests that human serum albumin (HSA), the most abundant protein in plasma, is a player in the innate immunity "orchestra." We previously demonstrated that HSA acts as a physiological buffer, partially neutralizing <i>Clostridioides difficile</i> toxins that reach the bloodstream after being produced in the colon. Here, we report the <i>in vitro</i> and <i>ex vivo</i> capability of HSA to neutralize the cytotoxic and hemolytic effects of SLO. HSA binds SLO with high affinity at a non-conventional site located in domain II, which was previously reported to interact also with <i>C. difficile</i> toxins. HSA:SLO recognition protects HEp-2 and A549 cells from cytotoxic effects and cell membrane permeabilization induced by SLO. Moreover, HSA inhibits the SLO-dependent hemolytic effect in red blood cells isolated from healthy human donors. The recognition of SLO by HSA may have a significant protective role in human serum and sustains the emerging hypothesis that HSA is an important constituent of the innate immunity system.