Streptococcus dysgalactiae subsp. equisimilis infection and its intersection with Streptococcus pyogenes

Abstract

SUMMARYStreptococcus dysgalactiae subsp. equisimilis (SDSE) is an increasingly recognized cause of disease in humans. Disease manifestations range from non-invasive superficial skin and soft tissue infections to life-threatening streptococcal toxic shock syndrome and necrotizing fasciitis. Invasive disease is usually associated with co-morbidities, immunosuppression, and advancing age. The crude incidence of invasive disease approaches that of the closely related pathogen, Streptococcus pyogenes. Genomic epidemiology using whole-genome sequencing has revealed important insights into global SDSE population dynamics including emerging lineages and spread of anti-microbial resistance. It has also complemented observations of overlapping pathobiology between SDSE and S. pyogenes, including shared virulence factors and mobile gene content, potentially underlying shared pathogen phenotypes. This review provides an overview of the clinical and genomic epidemiology, disease manifestations, treatment, and virulence determinants of human infections with SDSE with a particular focus on its overlap with S. pyogenes. In doing so, we highlight the importance of understanding the overlap of SDSE and S. pyogenes to inform surveillance and disease control strategies.

Keywords: Streptococcus; Streptococcus dysgalactiae; Streptococcus pyogenes; group C/G Streptococcus.

Fig 1

Midpoint-rooted phylogenetic tree of Streptococcus pyogenes, Streptococcus dysgalactiae subsp. equisimilis (SDSE) from human and animal reservoirs, Streptococcus dysgalactiae subsp. dysgalactiae (SDSD), and other clinically relevant large-colony Lancefield group C/G streptococci. Strains of SDSE isolated from animal hosts are phylogenetically distinct from strains causing human disease. Phylogeny inferred from selected National Center for Biotechnology Information RefSeq genomes (Table S1) using GTDB (24) bac120 marker genes and FastTree (25) v.2.1.11 under the WAG model. Scale represents amino acid substitutions per site. SDSE (animal) clade includes strains isolated from dogs, pigs, cows, fish (tilapia), and rhinos.

Fig 2

Virulence factors expressed by Streptococcus dysgalactiae subsp. equisimilis (SDSE) to facilitate adhesion, immune escape, and invasion in the human host. The multi-functional M protein inhibits complement deposition, binds host IgG, acts as adhesin to fibrinogen and collagen, and binds plasmin(ogen), which can then be activated by bacterial streptokinase (Skc/Skg). Plasmin(ogen) is also bound by streptococcal surface enolase (SEN) and glyceraldehyde-3-phosphate dehydrogenase (GapC) and mediates fibrinogen and tissue degradation. C5a peptidase ScpG degrades the chemotaxin C5a. DNases such as Sdc degrade neutrophil extracellular traps (NETs). Protein G and M protein bind and inhibit IgG function. DrsG inhibits the innate anti-microbial peptide, cathelicidin LL-37. Pili encoded by two loci, FCT and a variably present accessory FCT locus, putatively mediate tissue adhesion to fibronectin and collagen. GfbA, GapC, and other putative adhesins mediate adhesion to fibronectin. Lmb putatively binds laminin and is near identical to a laminin-binding protein in S. pyogenes. Streptolysin O (SLO) and streptolysin S (SLS) cause cell lysis and tissue destruction. Nicotinamide glycohydrolase (NADase) causes host cell apoptosis and enhances SLO. Superantigens other than SpeG are uncommonly present but can cause uncontrolled inflammation through activation of T cells. HylD and unsaturated glucuronyl hydrolase (UGL) degrade hyaluronate in the host extracellular matrix.

Fig 3

Schematic organization of the mgrC regulon of Streptococcus dysgalactiae subsp. equisimilis (SDSE) in comparison to the two most common configurations of the mga regulon in S. pyogenes. Homologous genes share the same color. The direction of the arrow indicates the orientation of the gene. A homolog of scpA, scpG, is located distant to the mgrC regulon in SDSE. Schemes are based on Frost et al. (51) and Geyer et al. (70).

Fig 4

Genetic arrangement of the FCT and accessory FCT loci in Streptococcus dysgalactiae subsp. equisimilis (SDSE) in comparison to homologous FCT types found in S. pyogenes. All SDSE strains carry the FCT locus, and 80%–90% carry the accessory FCT locus. Pilus biosynthetic enzymes include sortase genes. Schemes are based on Kratovac et al. (75), Nakata and Kreikemeyer (76), and Oppegaard et al. (73).

Fig 5

Streptococcus dysgalactiae subsp. equisimilis emm type diversity from published population or healthcare center-based epidemiological studies describing ≥20 SDSE or large-colony, beta-hemolytic group C/G Streptococcus isolates. Only the five most frequent emm types in each region are highlighted with all remaining emm types grouped as “other.” Studies were grouped by region: Western Europe (2, 3, 10, 60, 62, 67, 97, 107, 159, 202, 213–218) (16 studies, n = 4,618), Western Asia (219, 220) (2 studies, n = 284), Southern Asia (221, 222) (2 studies, n = 420), Eastern Asia (11, 12, 61, 71, 192, 210–212, 223–226) (12 studies, n = 2,344), Oceania (4, 227, 228) (3 studies, n = 677), Northern America (65, 66, 197) (3 studies, n = 423), Southern America (229–231) (3 studies, n = 90). There were no eligible studies from Africa.

Fig 6

Disease manifestations caused by Streptococcus dysgalactiae subsp. equisimilis (SDSE) in humans. Non-invasive manifestations are highlighted in blue, invasive manifestations in red, and post-infectious immune-mediated manifestations in green. Putative immune-mediated manifestations are denoted with question marks. Skin and soft tissue manifestations such as cellulitis can seed bacteremia and is a common source of invasive disease. Between 20% and 50% of invasive cases presenting with bacteremia may not have a clinically evident source of infection. SDSE infection has been linked with acute rheumatic fever, rheumatic heart disease, and acute post-streptococcal glomerulonephritis, but a firm causal relationship has not been established. APSGN, acute post-streptococcal glomerulonephritis; ARF, acute rheumatic fever; RHD, rheumatic heart disease.