Characterization of emergent toxigenic M1UK Streptococcus pyogenes and associated sublineages

Abstract

Streptococcus pyogenes genotype emm1 is a successful, globally distributed epidemic clone that is regarded as inherently virulent. An emm1 sublineage, M1UK, that produces increased levels of SpeA toxin was associated with increased scarlet fever and invasive infections in England in 2015/2016. Defined by 27 SNPs in the core genome, M1UK is now dominant in England. To more fully characterize M1UK, we undertook comparative transcriptomic and proteomic analyses of M1UK and contemporary non-M1UK emm1 strains (M1global). Just seven genes were differentially expressed by M1UK compared with contemporary M1global strains. In addition to speA, five genes in the operon that includes glycerol dehydrogenase were upregulated in M1UK (gldA, mipB/talC, pflD, and phosphotransferase system IIC and IIB components), while aquaporin (glpF2) was downregulated. M1UK strains have a stop codon in gldA. Deletion of gldA in M1global abrogated glycerol dehydrogenase activity, and recapitulated upregulation of gene expression within the operon that includes gldA, consistent with a feedback effect. Phylogenetic analysis identified two intermediate emm1 sublineages in England comprising 13/27 (M113SNPs) and 23/27 SNPs (M123SNPs), respectively, that had failed to expand in the population. Proteomic analysis of invasive strains from the four phylogenetic emm1 groups highlighted sublineage-specific changes in carbohydrate metabolism, protein synthesis and protein processing; upregulation of SpeA was not observed in chemically defined medium. In rich broth, however, expression of SpeA was upregulated ~10-fold in both M123SNPs and M1UK sublineages, compared with M113SNPs and M1global. We conclude that stepwise accumulation of SNPs led to the emergence of M1UK. While increased expression of SpeA is a key indicator of M1UK and undoubtedly important, M1UK strains have outcompeted M123SNPs and other emm types that produce similar or more superantigen toxin. We speculate that an accumulation of adaptive SNPs has contributed to a wider fitness advantage in M1UK on an inherently successful emm1 streptococcal background.

Rapid expansion and international spread of M1UK in the post-pandemic upsurge of Streptococcus pyogenes infections in United Kingdom

“…Two intermediate lineages, M113SNPs and M123SNPs, that share subsets of the 27 SNPs, were also identified 5,6 . M123SNPs expresses SpeA at the same level typical of M1UK, whereas M113SNPs does not 6 . By 2016, the M1UK lineage represented 84% of all emm1 invasive strains in England 5 , increasing to 91.5% by 2020 14 .…”

“…Among more than 250 recognised emm types, the emm1 genotype is most frequently associated with invasive infections in high-income countries 4 . emm1 strains are considered highly virulent 5,6 and often acquire inactivating mutations in the covRS two component regulator, which de-represses key virulence factors during invasive infection 7 . In the 1980s, emm1 emerged as a leading cause of invasive infection following several genomic changes that altered phage content and streptolysin O (SLO) expression, leading to a new clone that spread globally 8 .…”

“…Unexpectedly large seasonal upsurges in scarlet fever were documented annually in England between 2014-2018 11,12 coinciding with the expansion and recognition of a new lineage of emm1 termed M1UK among S. pyogenes isolates 5 . M1UK differed from other globally circulating emm1 strains 8 (hereafter referred to as M1global) by 27 signature SNPs and was characterised by increased expression of the scarlet fever toxin, streptococcal pyrogenic exotoxin A (speA) 5,6,13 . Two intermediate lineages, M113SNPs and M123SNPs, that share subsets of the 27 SNPs, were also identified 5,6 .…”

“…M1UK differed from other globally circulating emm1 strains 8 (hereafter referred to as M1global) by 27 signature SNPs and was characterised by increased expression of the scarlet fever toxin, streptococcal pyrogenic exotoxin A (speA) 5,6,13 . Two intermediate lineages, M113SNPs and M123SNPs, that share subsets of the 27 SNPs, were also identified 5,6 . M123SNPs expresses SpeA at the same level typical of M1UK, whereas M113SNPs does not 6 .…”

Emergentemm4group AStreptococcusevidences a survival strategy during interaction with immune effector cells

“…Group A Streptococcus (GAS) is a model for studying molecular pathogenomics of microbial epidemics as it has a relatively small genome (~2.0 Mb), there is active surveillance for GAS strains in many countries, and there is significant serological diversity (more than 200 emm types) based on the 5' sequence of the emm gene encoding the N-terminal region of the surface M protein [13][14][15][16]. GAS epidemiology has been characterized by large fluctuations in disease incidence and severity, such as the near disappearance of GAS-induced rheumatic fever from North America and Western Europe in the latter half of the 20th century [17][18][19].…”