The intricate pathogenicity of Group A Streptococcus: A comprehensive update

Abstract

Group A Streptococcus (GAS) is a versatile pathogen that targets human lymphoid, decidual, skin, and soft tissues. Recent advancements have shed light on its airborne transmission, lymphatic spread, and interactions with neuronal systems. GAS promotes severe inflammation through mechanisms involving inflammasomes, IL-1β, and T-cell hyperactivation. Additionally, it secretes factors that directly induce skin necrosis via Gasdermin activation and sustains survival and replication in human blood through sophisticated immune evasion strategies. These include lysis of erythrocytes, using red cell membranes for camouflage, resisting antimicrobial peptides, evading phagocytosis, escaping from neutrophil extracellular traps (NETs), inactivating chemokines, and cleaving targeted antibodies. GAS also employs molecular mimicry to traverse connective tissues undetected and exploits the host's fibrinolytic system, which contributes to its stealth and potential for causing autoimmune conditions after repeated infections. Secreted toxins disrupt host cell membranes, enhancing intracellular survival and directly activating nociceptor neurons to induce pain. Remarkably, GAS possesses mechanisms for precise genome editing to defend against phages, and its fibrinolytic capabilities have found applications in medicine. Immune responses to GAS are paradoxical: robust responses to its virulence factors correlate with more severe disease, whereas recurrent infections often show diminished immune reactions. This review focuses on the multifaceted virulence of GAS and introduces novel concepts in understanding its pathogenicity.

Keywords: Group A Streptococcus; Streptococcus pyogenes; bacterial pathogenesis; necrotizing fasciitis; toxins; virulence.

Figure 1.

Epidemiology of Group A Streptococcus (GAS). GAS infection induces many common diseases and infection outcomes. The figure indicates the estimated incidence per 100,000 inhabitants and for some diseases prevalence worldwide, deaths/year worldwide and disability-adjusted life years (DALYs)/year worldwide. Estimated incidence in the most affected risk group or setting is displayed. No incidence data was found for cellulitis, a more invasive form of erysipelas, hence not displayed. For NSTI, only GAS cases (30%) are indicated. Graph: note that the incidence scale has been cut to allow for comparisons between less common conditions. The bar below each illustration is proportional to the bars in the graph to allow for incidence comparisons. iGAS: invasive GAS infection, HICs: high-income countries, LICs: low-income countries. References: pharyngotonsillitis [36], impetigo [37], erysipelas [38,39], scarlet fever [25], ARF [1], RHD [12], PSGN [40], iGAS [1,23,24,41], puerperal fever [23,24,42], NSTI [18,43,44], STSS [45,46].

Figure 2.

Clinical features of Group A Streptococcus (GAS). GAS exhibits a wide array of pathogenic effects in blood, skin- and soft tissues, the lymphatic system as well as on immune cells and neurons. Clinical aspects are visualized next to an example of a virulence factor with that property and, in some cases, the specific host cell receptor. GAS spread through airborne transmission from asymptomatic pharyngeal carriagers, often school-aged children. In blood, GAS causes hemolysis, replicates, dissolves clots, evades phagocytes, hyperactivates T-cells and impairs B-cell responses. GAS disguises as host tissue elements, internalizes through pore-forming toxins, induces inflammation, pain, dermal necrosis and spreads through lymphatic vessels.

Figure 3.

Pathogenesis of Group A Streptococcus (GAS). GAS induces pathology through the actions of toxins and superantigens, immune evasion, host cell attachment, and tissue dissemination. Specific examples of virulence factors in these categories are visualized and, in some cases, the specific host cell receptors. GAS lyses red blood cells, hyperactivate T-cells, evade phagocytes, degrade neutrophil extracellular traps, internalize into host cells and lymphatic vessels, activate the NLRP3 inflammasome and IL-1β, disseminate through host tissues by degrading host proteins through protease activity and fibrinolysis through plasminogen activation. Pain is induced through activation of nociceptor neurons and skin necrosis through gasdermin activation.