title: Group A Streptococcus exploits human plasminogen for bacterial translocation across epithelial barrier via tricellular tight junctions.
abstract: 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.
authors.affiliation: Department of Oral and Molecular Microbiology, Osaka University Graduate School of Dentistry, 1-8, Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Sumitomo
authors.affiliation: Department of Oral and Molecular Microbiology, Osaka University Graduate School of Dentistry, 1-8, Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Nakata
authors.affiliation: Department of Oral and Molecular Microbiology, Osaka University Graduate School of Dentistry, 1-8, Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Miharu
authors.initials: M
authors.lastname: Higashino
authors.affiliation: Department of Oral and Molecular Microbiology, Osaka University Graduate School of Dentistry, 1-8, Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Yamaguchi
authors.affiliation: Department of Oral and Molecular Microbiology, Osaka University Graduate School of Dentistry, 1-8, Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Shigetada
authors.initials: S
authors.lastname: Kawabata
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D018988:Bacterial Translocation / Q000235:genetics; D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology; D054884:Host-Pathogen Interactions / Q000235:genetics*; D006801:Humans; D062794:MARVEL Domain Containing 2 Protein / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D010751:Phosphopyruvate Hydratase / Q000235:genetics / Q000378:metabolism*; D010958:Plasminogen / Q000235:genetics / Q000378:metabolism*; D013045:Species Specificity; D013297:Streptococcus pyogenes / Q000378:metabolism / Q000472:pathogenicity; D020349:Surface Plasmon Resonance; D019108:Tight Junctions / Q000378:metabolism / Q000382:microbiology
chemical_list: D001426:Bacterial Proteins; D002352:Carrier Proteins; D062794:MARVEL Domain Containing 2 Protein; D010958:Plasminogen; C112984:streptococcal surface enolase; D010751:Phosphopyruvate Hydratase
references.citation: FASEB J. 2008 Sep;22(9):3146-53
references.pmid: 18511548
references.citation: J Biol Chem. 1991 Mar 15;266(8):4922-8
references.pmid: 1848229
references.citation: J Exp Med. 1992 Aug 1;176(2):415-26
references.pmid: 1500854
references.citation: Blood Coagul Fibrinolysis. 1992 Oct;3(5):605-14
references.pmid: 1333289
references.citation: J Biol Chem. 1993 Dec 5;268(34):25417-24
references.pmid: 8244975
references.citation: J Biol Chem. 1998 Jun 5;273(23):14503-15
references.pmid: 9603964
references.citation: Infect Immun. 1999 Aug;67(8):3915-20
references.pmid: 10417156
references.citation: Trends Microbiol. 2005 Jul;13(7):308-13
references.pmid: 15936195
references.citation: Lancet. 2005 Jul 9-15;366(9480):155-68
references.pmid: 16005340
references.citation: J Infect Dis. 2005 Sep 1;192(5):760-70
references.pmid: 16088825
references.citation: Curr Opin Cell Biol. 2005 Oct;17(5):489-98
references.pmid: 16102958
references.citation: Lancet Infect Dis. 2005 Nov;5(11):685-94
references.pmid: 16253886
references.citation: J Cell Biol. 2005 Dec 19;171(6):939-45
references.pmid: 16365161
references.citation: J Bacteriol. 2007 Feb;189(4):1435-40
references.pmid: 17012384
references.citation: Trends Microbiol. 2007 Jul;15(7):318-25
references.pmid: 17524649
references.citation: Infect Immun. 2007 Dec;75(12):5698-710
references.pmid: 17893125
references.citation: Expert Opin Drug Metab Toxicol. 2008 Apr;4(4):395-411
references.pmid: 18433344
references.citation: Infect Immun. 2009 Jan;77(1):32-44
references.pmid: 18852238
references.citation: J Biol Chem. 2008 Dec 26;283(52):36272-9
references.pmid: 18974092
references.citation: Biochim Biophys Acta. 2009 Apr;1788(4):832-41
references.pmid: 19059200
references.citation: J Biol Chem. 2009 Jun 19;284(25):17129-37
references.pmid: 19363026
references.citation: J Biol Chem. 2011 Jan 28;286(4):2750-61
references.pmid: 21084306
references.citation: J Biol Chem. 2011 Oct 28;286(43):37566-77
references.pmid: 21880740
references.citation: Cell Host Microbe. 2012 Apr 19;11(4):325-36
references.pmid: 22520461
references.citation: Cell Rep. 2012 Mar 29;1(3):185-90
references.pmid: 22832192
references.citation: J Biol Chem. 2013 May 10;288(19):13317-24
references.pmid: 23532847
references.citation: PLoS One. 2015;10(3):e0121764
references.pmid: 25807546
references.citation: Microbes Infect. 2000 Jul;2(9):1119-24
references.pmid: 10967292
references.citation: Nat Rev Mol Cell Biol. 2001 Apr;2(4):285-93
references.pmid: 11283726
references.citation: Plasmid. 2001 Sep;46(2):140-8
references.pmid: 11591139
references.citation: Nature. 2001 Dec 6;414(6864):648-52
references.pmid: 11740562
references.citation: FEMS Microbiol Rev. 2001 Dec;25(5):531-52
references.pmid: 11742690
references.citation: Curr Opin Microbiol. 2003 Feb;6(1):77-81
references.pmid: 12615224
references.citation: Mol Microbiol. 2003 Jul;49(2):411-23
references.pmid: 12828639
references.citation: Microb Pathog. 2003 Dec;35(6):293-303
references.pmid: 14580393
references.citation: Infect Immun. 2004 Jan;72(1):94-105
references.pmid: 14688086
references.citation: Microbiology. 2004 Feb;150(Pt 2):365-71
references.pmid: 14766914
references.citation: Am J Physiol Cell Physiol. 2004 Jun;286(6):C1213-28
references.pmid: 15151915
references.citation: Science. 2004 Aug 27;305(5688):1283-6
references.pmid: 15333838
references.citation: J Mol Biol. 2004 Oct 29;343(4):997-1005
references.pmid: 15476816
references.citation: J Cell Biol. 1974 Jan;60(1):168-80
references.pmid: 4203358
references.citation: J Cell Sci. 1973 Nov;13(3):763-86
references.pmid: 4203962
references.citation: J Membr Biol. 1978 Mar 10;39(2-3):219-32
references.pmid: 641977
references.citation: Int J Oral Surg. 1982 Apr;11(2):110-4
references.pmid: 6809670
references.citation: Acta Anat (Basel). 1985;122(1):35-8
references.pmid: 4003026
references.citation: J Dent Res. 1990 Jun;69(6):1283-6
references.pmid: 2113068
references.citation: Gene. 1991 Jun 15;102(1):99-104
references.pmid: 1864514