Population Genomics of emm4 Group A Streptococcus Reveals Progressive Replacement with a Hypervirulent Clone in North America

Abstract

Severe invasive infections caused by group A Streptococcus (GAS) result in substantial morbidity and mortality in children and adults worldwide. Previously, GAS clonal strain replacement has been attributed to acquisition of exogenous DNA leading to novel virulence gene acquisition or increased virulence gene expression.

CovS inactivation reduces CovR promoter binding at diverse virulence factor encoding genes in group A Streptococcus

“…lctO, alaS, rivR or ffh) [14]. Given that RivR is naturally inactivated in both emm3 and emm4 GAS, emm types in which CovS inactivation is common amongst clinical strains and markedly impacts strain virulence [63][64][65], and the fact that the 16 genes whose transcript levels were most increased by abrogating CovR~P [30], all are directly regulated by CovR (black genes in Fig 3 ), we believe that both data sets support the…”

“…lctO , alaS , rivR or ffh ) [ 14 ]. Given that RivR is naturally inactivated in both emm3 and emm4 GAS, emm types in which CovS inactivation is common amongst clinical strains and markedly impacts strain virulence [ 63 – 65 ], and the fact that the 16 genes whose transcript levels were most increased by abrogating CovR~P [ 30 ], all are directly regulated by CovR (black genes in Fig 3 ), we believe that both data sets support the concept that relief of direct CovR repression induced by decreased CovR~P levels following CovS inactivation or exposure to LL-37 is the major mechanism by which CovR impacts gene expression.…”

Characterization of the Type I Restriction Modification System Broadly Conserved among Group A Streptococci

“…Complete genome sequences were determined for several GAS strains in this study using a combination of short-read (Illumina) and long-read (Oxford Nanopore) sequence data ( Table 2 ; Table S2a ). Genomic DNA extraction, library construction, and sequencing (Illumina MiSeq or ONT GridION) were performed as previously described ( 62 , 63 ). Average depths of coverage for completed genomes were >100-fold and a minimum of 50-fold for both short- and long-read sequences.…”

Novelemm4 lineage associated with an upsurge in invasive group A streptococcal disease in the Netherlands, 2022

“…Reference genomes originate from Debroy et al . (2021) ( 2 ) and are shown without metadata. The hypervirulent clone lineage is colored blue and the M4 NL22 lineage is colored red.…”

“…Recently, a hypervirulent emm 4 clone (henceforth referred to as the “hypervirulent clone”) was described, which has replaced nearly all other emm 4 S. pyogenes strains in the USA and UK 3 . We hypothesized that this hypervirulent emm 4 clone was responsible for the increase of emm 4 iGAS cases in the Netherlands.…”