Disease manifestations and pathogenic mechanisms of Group A Streptococcus

Abstract

Streptococcus pyogenes, also known as group A Streptococcus (GAS), causes mild human infections such as pharyngitis and impetigo and serious infections such as necrotizing fasciitis and streptococcal toxic shock syndrome. Furthermore, repeated GAS infections may trigger autoimmune diseases, including acute poststreptococcal glomerulonephritis, acute rheumatic fever, and rheumatic heart disease. Combined, these diseases account for over half a million deaths per year globally. Genomic and molecular analyses have now characterized a large number of GAS virulence determinants, many of which exhibit overlap and redundancy in the processes of adhesion and colonization, innate immune resistance, and the capacity to facilitate tissue barrier degradation and spread within the human host. This improved understanding of the contribution of individual virulence determinants to the disease process has led to the formulation of models of GAS disease progression, which may lead to better treatment and intervention strategies. While GAS remains sensitive to all penicillins and cephalosporins, rising resistance to other antibiotics used in disease treatment is an increasing worldwide concern. Several GAS vaccine formulations that elicit protective immunity in animal models have shown promise in nonhuman primate and early-stage human trials. The development of a safe and efficacious commercial human vaccine for the prophylaxis of GAS disease remains a high priority.

FIG 1

The arsenal of virulence factors expressed by GAS to thwart the host innate immune response. The secreted proteases SpyCEP/ScpC and ScpA degrade the chemokines IL-8 and C5a, respectively, hindering phagocyte recruitment to the site of infection. Surface-associated M protein binds Fc domains of Ig and the complement-regulatory proteins C4BP and factor H to interfere with complement deposition. Mac-1/2 degrades Ig and binds phagocyte Fc receptors to block phagocytosis. Antimicrobial peptide resistance is mediated by hyaluronic acid capsule, d-alanylation of surface lipoteichoic acid by DltABCD, inactivation though SIC binding, and degradation by the cysteine protease SpeB. Ig and antimicrobial peptides are degraded by SpeB to facilitate the establishment of GAS infection in vivo. Secreted Sda1 DNase activity degrades NETs to promote neutrophil survival. The cytolysins SLS and SLO mediate lysis and apoptosis of neutrophils and macrophages.

FIG 2

The interplay between host and bacterial factors leads to tissue destruction, vascular leakage, and hyperinflammation in invasive GAS disease. Plasminogen is recruited to the GAS cell surface directly (PAM/Prp, SEN, and GAPDH) or indirectly (fibrinogen receptors). Activation of plasminogen is mediated by bacterial (Ska) or host (uPA/tPA) plasminogen activators. Subsequent plasmin activity contributes to fibrin degradation, tissue destruction, and vascular leakage. Complexes of soluble M protein and fibrinogen cross-link to β2-integrins on the neutrophil surface, triggering the release of proinflammatory mediators. Soluble M protein fragments also mediate the activation of the extrinsic pathway of coagulation by triggering tissue factor synthesis and platelet aggregation. Contact activation at the GAS cell surface (M protein, fibrinogen, and kininogen) leads to the formation of a fibrin network and bradykinin generation, contributing to vascular leakage. The secreted toxins SLO and SLS trigger apoptosis of host cells, leading to tissue destruction. SLO also mediates neutrophil platelet aggregation. Secreted superantigens (Sags, Spes, and SmeZ) bind to the beta-chain of antigen-presenting cells (APC) and CD4⁺ T cells, triggering the release of proinflammatory mediators and overstimulation of the immune response.