Group A Streptococcus exploits human plasminogen for bacterial translocation across epithelial barrier via tricellular tight junctions

• Published in: Scientific reports 2016-01, Vol.6 (1), p.20069, Article 20069
• Main Authors: Sumitomo, Tomoko, Nakata, Masanobu, Higashino, Miharu, Yamaguchi, Masaya, Kawabata, Shigetada
• Format: Article
• Language: English
• Subjects: 13/1; 631/326/421; 631/326/88; Amino acids; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Bacterial Translocation - genetics; Binding sites; Caco-2 Cells; Carrier Proteins - genetics; Epithelial cells; Epithelial Cells - metabolism; Epithelial Cells - microbiology; Host-Pathogen Interactions - genetics; Humanities and Social Sciences; Humans; Infections; Localization; Lysine; MARVEL Domain Containing 2 Protein - genetics; MARVEL Domain Containing 2 Protein - metabolism; multidisciplinary; Mutagenesis, Site-Directed; Pathogens; Phosphopyruvate hydratase; Phosphopyruvate Hydratase - genetics; Phosphopyruvate Hydratase - metabolism; Plasminogen - genetics; Plasminogen - metabolism; Proteins; Quantitative analysis; Science; Site-directed mutagenesis; Species Specificity; Streptococcus; Streptococcus infections; Streptococcus pyogenes - metabolism; Streptococcus pyogenes - pathogenicity; Surface Plasmon Resonance; Tight junctions; Tight Junctions - metabolism; Tight Junctions - microbiology; Translocation
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep20069

Group A Streptococcus (GAS) is a human-specific pathogen responsible for local suppurative and life-threatening invasive systemic diseases. Interaction of GAS with human plasminogen (PLG) is a salient characteristic for promoting their systemic dissemination. In the present study, a serotype M28 strain was found predominantly localized in tricellular tight junctions of epithelial cells cultured in the presence of PLG. Several lines of evidence indicated that interaction of PLG with tricellulin, a major component of tricellular tight junctions, is crucial for bacterial localization. A site-directed mutagenesis approach revealed that lysine residues at positions 217 and 252 within the extracellular loop of tricellulin play important roles in PLG-binding activity. Additionally, we demonstrated that PLG functions as a molecular bridge between tricellulin and streptococcal surface enolase (SEN). The wild type strain efficiently translocated across the epithelial monolayer, accompanied by cleavage of transmembrane junctional proteins. In contrast, amino acid substitutions in the PLG-binding motif of SEN markedly compromised those activities. Notably, the interaction of PLG with SEN was dependent on PLG species specificity, which influenced the efficiency of bacterial penetration. Our findings provide insight into the mechanism by which GAS exploits host PLG for acceleration of bacterial invasion into deeper tissues via tricellular tight junctions.