Streptococcus pyogenes (Group A Streptococcus, GAS) is a human restricted pathogen that commonly causes mild infections of the respiratory tract (pharyngitis) or the skin (impetigo). However, GAS infections can also lead to more severe, invasive infections such as necrotising fasciitis and streptococcal toxic shock-like syndrome. Recently a sharp increase in scarlet fever cases and invasive GAS infections has been reported in the United Kingdom, which was associated with the emergence of a new sub-lineage of the epidemic GAS emm1 serotype (designated “M1UK”). After its first detection in 2010, M1UK has since disseminated globally and is now becoming the dominant GAS emm1 genotype in invasive GAS infections, such as pneumonia and meningitis.
A stepwise accumulation of 27 single nucleotide polymorphisms (SNPs) in the progenitor “M1global” clone led to the emergence of M1UK, which is characterised by enhanced expression of the superantigen SpeA. These SNPs have occurred in regulatory, metabolic and hypothetical genes but their contribution to the epidemic success of M1UK remains largely unknown. Herein we characterise some of the key SNPs that may have contributed to a wider fitness advantage for M1UK using site-directed mutagenesis to either repair or introduce these SNPs in isogenic mutant strains. These loss-and-gain of function studies led to our discovery that a single SNP in the 5’ transcriptional leader sequence of the transfer-messenger RNA gene ssrA is responsible for increased transcriptional read-through in M1UK, driving increased expression of the downstream adjacent speA superantigen gene. Detailed molecular characterisation of these SNPs will contribute to our understanding of M1UK emergence and shed light on the pathogenic mechanisms of GAS infection and may help identifying novel therapeutic targets to combat this pandemic.