Molecular and genomic characterization of pathogenic traits of group A Streptococcus pyogenes

Abstract

Group A streptococcus (GAS) or Streptococcus pyogenes causes various diseases ranging from self-limiting sore throat to deadly invasive diseases. The genome size of GAS is 1.85-1.9 Mb, and genomic rearrangement has been demonstrated. GAS possesses various surface-associated substances such as hyaluronic capsule, M proteins, and fibronectin/laminin/immunoglobulin-binding proteins. These are related to the virulence and play multifaceted and mutually reflected roles in the pathogenesis of GAS infections. Invasion of GAS into epithelial cells and deeper tissues provokes immune and non-immune defense or inflammatory responses including the recruitment of neutrophils, macrophages, and dendritic cells in hosts. GAS frequently evades host defense mechanisms by using its virulence factors. Extracellular products of GAS may perturb cellular and subcellular functions and degrade tissues enzymatically, which leads to the aggravation of local and/or systemic disorders in the host. In this review, we summarize some important cellular and extracellular substances that may affect pathogenic processes during GAS infections, and the host responses to these.

Figure 1.

Phage-related genomic rearrangements result in the diversity of the GAS chromosome. The virulence genes in the phage regions A and B are exchangeable, forming phages A′ and B′.

Figure 2.

Immunoelectron microscopy of the fibrillar structures on the surface of GAS. M proteins (A) and pili (B) are visualized by incubation with specific antibodies, followed by incubation with gold-conjugated secondary antibodies. Bar, 0.5 µm.

Figure 3.

Schematic illustration of FN, FbaA, and FbaB. (A) FN is constituted by subunits I, II, and III that are represented as hexagons, pentagons, and squares, respectively. FN can interact with various proteins. (B) FbaA possesses 3 repeat domains (RDs). Among 6 genetically modified recombinant FbaA proteins, those possessing RDs bind FN. (C) FbaB contains an RGD motif in addition to an FN-binding motif.

Figure 4.

SLS promotes translocation of GAS via a paracellular route. SLS signals the activation of host calpains and augments the penetration of GAS across the epithelial barrier via degradation of epithelial intercellular junctions.

Figure 5.

Autophagosome formation in GAS-infected HeLa cells. In the control cell culture (A), a limited number of autophagosomes is seen in the cytoplasm, while multiple autophagosomes (diameter = 0.5 µm) exist in the cytoplasm under starvation (B). In GAS-infected cells, large autophagosome-like vacuoles (diameter > 5 µm) containing GAS are found in the cytoplasm (C). Green; EGFP-LC3 (autophagosome marker), Red; PI staining. Scale bar = 10 µm.

Figure 6.

Membrane trafficking of autophagosome-like vacuoles in GAS-infected cells. The endocytic pathway is tightly regulated by several Rab GTPases in non-infected conditions (bottom panel). In case of GAS infection, infection-specific Rab GTPases (Rab23, Rab9a, and Rab17) are required for maintaining the large autophagic vacuoles to degrade the intracellular GAS (right panel).

Figure 7.

Systemic dissemination of GAS during infection. Following bacterial entry into the subepithelial tissue, GAS expresses SpeB for the establishment of localized infection. Spontaneous mutations in the covR/S operon trigger loss of SpeB expression and strong transcriptional upregulation of several virulence factors including Sda1 responsible for bacterial escape from NETs. Loss of SpeB allows the accumulation of surface plasmin through Ska, which ultimately results in tissue destruction and systemic GAS infection.