Pathogenesis, epidemiology and control of Group A Streptococcus infection

Abstract

Streptococcus pyogenes (Group A Streptococcus; GAS) is exquisitely adapted to the human host, resulting in asymptomatic infection, pharyngitis, pyoderma, scarlet fever or invasive diseases, with potential for triggering post-infection immune sequelae. GAS deploys a range of virulence determinants to allow colonization, dissemination within the host and transmission, disrupting both innate and adaptive immune responses to infection. Fluctuating global GAS epidemiology is characterized by the emergence of new GAS clones, often associated with the acquisition of new virulence or antimicrobial determinants that are better adapted to the infection niche or averting host immunity. The recent identification of clinical GAS isolates with reduced penicillin sensitivity and increasing macrolide resistance threatens both frontline and penicillin-adjunctive antibiotic treatment. The World Health Organization (WHO) has developed a GAS research and technology road map and has outlined preferred vaccine characteristics, stimulating renewed interest in the development of safe and effective GAS vaccines.

Fig. 1. GAS virulence factors and their roles in cell adherence, invasion and immune evasion.

a, Surface-expressed M protein and the capsule facilitate attachment of Group A Streptococcus (GAS) to epithelial cells via binding to CD46, specific glycan structures and CD44, respectively. Secretion of the toxins streptococcal pyrogenic exotoxin B (SpeB) and streptolysin S (SLS) at the epithelial surface destabilizes the junctional proteins of epithelial cells, resulting in the loss of cell–cell adhesion and translocation of GAS across the host epithelial barrier. Following bacterial invasion into epithelial cells, joint action of streptolysin O (SLO) and NAD glycohydrolase (NADase) leads to the disruption of the Golgi network, which further impairs epithelial barrier integrity. b, Invasion of deeper underlying tissue may also occur through streptolysin (SLS and SLO) and NADase-induced cell death, or via SpeB-induced, gasdermin A (GSDMA)-dependent pyroptotic cell death of epithelial cells. The resulting tissue damage mounts a robust inflammatory response characterized by abundant infiltration of innate and adaptive immunity cells, attracted by various stimuli, such as human cathelicidin LL-37, pro-inflammatory cytokine interleukin-8 (IL-8) and SpeB-activated IL-36γ. c, GAS has evolved multiple mechanisms to elude the host immune system. These include the degradation of LL-37 by SpeB, IL-8 cleavage by S. pyogenes cell envelope proteinase (SpyCEP) and cleavage of the complement component 5a (C5a) by a C5a peptidase (ScpA). Coating of the bacterial surface with host factors, such as histones, plasminogen and fibrinogen, via binding to surface-expressed M protein further prevents immune recognition. Host defence proteins, such as fibrin and histones, and the human contact system are also proteolytic target molecules for the surface-bound streptokinase (SK)–plasmin complex which assists bacterial dissemination. d, Streptolysin SLS activity triggers neural release of calcitonin gene-related peptide (CGRP) into infected tissues, suppressing neutrophil recruitment and bactericidal activity. e, Extracellular deoxyribonucleases (DNases) degrade the DNA backbone of neutrophil extracellular traps (NETs), allowing GAS to escape neutrophil killing. f, The coordinated activities of SLO and NADase further prevent maturation of phagolysosomes, inhibit IL-8 secretion and promote GAS survival in macrophages, where streptolysins SLO and SLS and M protein activate the inflammasome pathway to induce IL-1β production and pyroptosis. SpeB additionally amplifies inflammatory signalling by cleaving and activating pro-IL-1β in an inflammasome-independent manner. g, Survival strategies employed by GAS to escape adaptive immunity include the secretion of the IgG-degrading enzymes IdeS, Mac-2 and EndoS, which enables bacterial escape from IgG opsonization and recognition by FcγR on phagocytes. h, Superantigens, by contrast, cause excessive activation of the adaptive immune system by cross-linking MHC class II molecules on antigen-presenting cells (APCs) and T cell receptors (TCRs) in a nonspecific fashion leading to an event known as a ‘cytokine storm’. i, Upon bloodstream entry, S protein-mediated coating of GAS cells with lysed red blood cell (RBC) fragments, such as those derived from SLO and SLS haemolytic activity, serves as an immune camouflage tactic which allows GAS to survive in and disseminate from blood vessels. CTD, carboxy-terminal domain; GSDMD, gasdermin D; NTD, amino-terminal domain.

Fig. 2. Overview of pathogenic mechanisms of MAIT cell activation during GAS infection.

Mechanisms of mucosal-associated invariant T cell (MAIT cell) activation during Group A Streptococcus (GAS) infections. a, The first phase is driven by superantigens such as streptococcal pyrogenic exotoxin A (SpeA), SpeJ and SpeC interacting with the MAIT cell T cell receptor (TCR) in an MR1-independent manner. The activation of the MAIT cell TCR drives the rapid release of prodigious quantities of TNF, and low levels of IFNγ. b, In the second phase, interleukin-18 (IL-18) and IL-12, which are released by immune and epithelial cells, bind to their cognate receptors on the surface of MAIT cells. The activation of IL-12 and IL-18 receptors on the surface of MAIT cells results in an IFNγ-dominated cytokine response. c, MAIT cells from patients with streptococcal toxic shock-like syndrome (STSS), acute rheumatic fever (ARF) and pharyngitis are highly activated, exhibiting higher expression of CD25, CD69 and other activation markers compared with healthy individuals, which is associated with higher production of INFγ, TNF and IL-2. The increased production of INFγ, TNF and IL-2 contributes directly to immunopathology during GAS pharyngitis, and bouts of ARF. d, MAIT cell-derived pro-inflammatory cytokines also provide stimulatory signals to innate immune cells to enhance their production of other inflammatory cytokines. The release of IL-1β and lymphotoxin-α (LTα; formerly known as TNFβ) by innate immune cells and of INFγ, TNF and IL-2 by MAIT cells contributes to the cytokine storm which underpins the immunopathology associated with STSS. Aberrant cytokine response contributes to morbidity and mortality during STSS.

Fig. 3. Global genetic diversity of GAS.

CIRCOS plot of 299 global Group A Streptococcus (GAS) lineages based on 2,083 diverse GAS genome sequences with connecting lines linking genomic lineages with the geographical region of isolation. Colours relate to the geographical region of isolation. Genomic lineages are represented in the upper hemisphere of the plot (alternating grey) and split into lineages that have been identified in multiple or single geographical regions. Bar plot represents the total number of ‘unique’ single-continent genomic lineages per geographical region (coloured).

Fig. 4. Mechanisms of GAS antibiotic resistance.

a, Macrolide resistance: methylation of 23S ribosomal RNA (rRNA) by methylase encoding erythromycin resistance methylase (erm) genes mediates resistance to macrolides, lincosamides and streptogramin B, giving rise to the MLS_B resistance Group A Streptococcus (GAS) phenotype. Active macrolide efflux conferred by mefA (macrolide efflux protein A) gene expression drives resistance to 14 and 15 carbon-ring macrolides only. b, Tetracycline resistance: ribosomal protection proteins TetM and TetO displace tetracyclines from the 30S ribosomal binding site, whereas TetK and TetL expression mediates the active efflux of tetracycline from the GAS cytosol. c, Fluoroquinolone (FQ) resistance: mutations in parC, encoding topoisomerase IV, confer low-level FQ resistance in GAS, whereas additional stepwise mutations in gyrA, encoding DNA gyrase, lead to the high FQ resistance GAS phenotype. d, Sulfamethoxazole resistance: the horizontally acquired energy-coupling factor transporter S component (ThfT) sequesters extracellular folate intermediate compounds such as 5,6,7,8-tetrahydrofolate and 7,8-dihydrofolate which feed into the folate cycle, bypassing the inhibitory effects of sulfamethoxazole on folate synthesis. e, Reduction in β-lactam sensitivity: missense mutations in penicillin binding protein 2X (PBP2x) result in reduced GAS susceptibility to β-lactam antibiotics, amoxicillin and ampicillin below resistant minimum inhibitory concentration (MIC) breakpoints. HGT, horizontal gene transfer.