Streptolysin production and activity is central to in vivo pathotype and disease outcome in GAS infections

Streptococcus pyogenes (GAS) is among the most diverse of all human pathogens, responsible for a range of clinical manifestations, from mild superficial infections such as pharyngitis to serious invasive infections such as necrotising fasciitis and sepsis. The drivers of these different disease phenotypes are not known. The GAS cholesterol-dependent cytolysin, streptolysin O (SLO), has well established cell and tissue destructive activity. We investigated the role of SLO in determining disease outcome , by using two different clinical lineages; the recently emerged hypervirulent outbreak type 32.2 strains, which result in sepsis, and the type 1.0 strains which cause septic arthritis. Using clinically relevant mouse models of sepsis and a novel septic arthritis model, we demonstrated that the amount and activity of SLO is vital in determining the pathotype of infection. The 32.2 strain produced large quantities of highly haemolytic SLO that resulted in rapid development of sepsis. By contrast, the lower levels and haemolytic activity of 1.0 SLO led to translocation of bacteria to joints. Importantly, sepsis associated strains that were attenuated by deletion or inhibition of SLO also translocated to the joint, confirming the key role of SLO in determining infection niche. Our findings demonstrate that SLO is key to pathotype and disease outcome. Careful consideration should be given to novel therapy or vaccination strategies that target SLO. Whilst neutralising SLO activity may reduce severe invasive disease, it has the potential to promote chronic inflammatory conditions such as septic arthritis.