The burden of group A Streptococcus (GAS) infections: The challenge continues in the twenty-first century

Abstract

Streptococcus pyogenes is a Gram-positive bacterium, also known as Group A Streptococcus (GAS), that has become a significant threat to the healthcare system, infecting more than 18 million people and resulting in more than 500,000 deaths annually worldwide. GAS infection rates decreased gradually during the 20th century in Western countries, largely due to improved living conditions and access to antibiotics. However, post-COVID-19, the situation has led to a steep increase in GAS infection rates in Europe, the United States, Australia, and New Zealand, which triggers a global concern. GAS infections are normally moderate, with symptoms of fever, pharyngitis, and pyoderma; nevertheless, if left untreated or with continued exposure to GAS or with recurring infections it can result in fatal outcomes. GAS produces a variety of virulence factors and exotoxins that can lead to deadly infections such as necrotizing fasciitis, impetigo, cellulitis, pneumonia, empyema, streptococcal toxic shock syndrome, bacteremia, and puerperal sepsis. In addition, post-immune mediated disorders such as post-streptococcal glomerulonephritis, acute rheumatic fever, and rheumatic heart disease contribute to extremely high death rates in developing nations. Despite substantial research on GAS infections, it is still unclear what molecular pathways are responsible for their emergence and how to best manage them. This review thus provides insights into the most recent research on the pathogenesis, virulence, resistance, and host interaction mechanisms of GAS, as well as novel management options to assist scientific communities in combating GAS infections.

Keywords: Biological sciences; Health sciences; Medical microbiology; Medical specialty; Medicine; Microbiology; Natural sciences; Pharmacology; Therapeutics.

Graphical abstract

Figure 1

Diversity in the antimicrobial resistances exhibited by GAS (A) The PBP2x-T553K variant diminishes penicillin’s binding affinity and leads to reduced Beta-lactam susceptibility in GAS. (B) Ribosomal methylation of the 23S ribosomal RNA by erm genes inhibits translation, thereby conferring resistance to macrolides. In parallel mef(A)gene expression confers macrolide resistance through efflux activation. (C) During GAS infection, TetM and TetO, ribosomal protective proteins, displace tetracyclines from the 30S ribosomal binding site, whereas TetK and TetL enhance active efflux of tetracyclines from the cytosol. (D) Point mutations in parC and gyrA gene leads to suppression of topoisomerases and DNA gyrase respectively, leading to fluoroquinolone resistance in GAS. (E) The ThfT gene aids in the acquisition of folate compounds from the host leading to sulfamethoxazole resistance in GAS.

Figure 2

TLR and MyD88 signaling cascades stimulate the expression of IFN- and pro-inflammatory cytokines such as TNF and IL-6 TNF encourages macrophage recruitment to the infection. Type I IFN signaling induced by IFN- and other type I IFNs initiates unidentified responses that end in balanced neutrophil infiltration and protective immune responses against GAS. TLR9 promotes GAS killing by ROS production. GAS induces IL-1β in an NLRP3-dependent manner.

Figure 3

The M proteins that are surface expressed helps in initial attachment of GAS to epithelial cells Secretory toxins such as SpeB, SLS/SLO and NADase helps in breaking the epithelial barriers thereby helping in the translocation of GAS to host cells. (A) The M protein further prevents host recognition through molecular mimicry with host factors such as plasminogen and fibrinogen. Streptokinase (SK)–plasmin complex which assists bacterial dissemination. (B) GAS has evolved a number of methods to avoid detection by the host immune system. These include SpeB-mediated LL-37 degradation, SpyCEP-mediated IL-8 cleavage, and ScpA-mediated cleavage of the complement component 5a (C5a) by a C5a peptidase. (C) The hemolytic activity of SLO and SLS acts as an immunological camouflage technique, allowing GAS to live in and spread from blood vessels. (D) Superantigens promotes excessive adaptive immune system activation by nonspecifically cross-linking MHC class II molecules on antigen-presenting cells (APCs) and T cell receptors (TCRs), resulting in a cytokine storm. (E) DNases destroy the DNA backbone of neutrophil extracellular traps (NETs), allowing GAS to avoid neutrophil killing.