title: Group B Streptococcus hijacks the host plasminogen system to promote brain endothelial cell invasion.
abstract: Group B Streptococcus (GBS) is the leading cause of meningitis in neonates. We have previously shown that plasminogen, once recruited to the GBS cell surface and converted into plasmin by host-derived activators, leads to an enhancement of bacterial virulence. Here, we investigated whether plasmin(ogen) bound at the GBS surface contributes to blood-brain barrier penetration and invasion of the central nervous system. For that purpose, GBS strain NEM316 preincubated with or without plasminogen plus tissue type plasminogen activator was analyzed for the capacity to adhere to, invade and transmigrate the human brain microvascular endothelial cell (hBMEC) monolayer, and to penetrate the central nervous system using a neonatal mouse model. At earlier times of infection, plasmin(ogen)-treated GBS exhibited a significant increase in adherence to and invasion of hBMECs. Later, injury of hBMECs were observed with plasmin(ogen)-treated GBS that displayed a plasmin-like activity. The same results were obtained when hBMECs were incubated with whole human plasma and infected with untreated GBS. To confirm that the observed effects were due to the recruitment and activation of plasminogen on GBS surface, the bacteria were first incubated with epsilon-aminocaproic acid (εACA), an inhibitor of plasminogen binding, and thereafter with plasmin(ogen). A significant decrease in the hBMECs injury that was correlated with a decrease of the GBS surface proteolytic activity was observed. Furthermore, plasmin(ogen)-treated GBS infected more efficiently the brain of neonatal mice than the untreated bacteria, indicating that plasmin(ogen) bound to GBS surface may facilitate the traversal of the blood-brain barrier. A higher survival rate was observed in offspring born from εACA-treated mothers, compared to untreated mice, and no brain infection was detected in these neonates. Our findings suggest that capture of the host plasmin(ogen) by the GBS surface promotes the crossing of the blood-brain barrier and contributes to the establishment of meningitis.
authors: ICBAS-Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, Porto, Portugal.
authors: Vanessa
authors: V
authors: Magalhães
authors: Elva Bonifácio
authors: EB
authors: Andrade
authors: Joana
authors: J
authors: Alves
authors: Adilia
authors: A
authors: Ribeiro
authors: Kwang Sik
authors: KS
authors: Kim
authors: Margarida
authors: M
authors: Lima
authors: Patrick
authors: P
authors: Trieu-Cuot
authors: Paula
authors: P
authors: Ferreira
mesh_terms: D000818:Animals; D001422:Bacterial Adhesion; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000382:microbiology; D001921:Brain / Q000098:blood supply / Q000166:cytology* / Q000378:metabolism / Q000382:microbiology; D042783:Endothelial Cells / Q000382:microbiology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D055806:Microvessels / Q000166:cytology; D010958:Plasminogen / Q000378:metabolism*; D013292:Streptococcus agalactiae / Q000378:metabolism / Q000502:physiology*
chemical_list: D010958:Plasminogen
references: J Infect Dis. 1999 Apr;179(4):907-14
references: 10068586
references: Nat Commun. 2011 Sep 06;2:462
references: 21897373
references: Hematology Am Soc Hematol Educ Program. 2001;:1-9
references: 11722975
references: Microbes Infect. 2007 May;9(6):714-20
references: 17400016
references: Methods. 2000 Jun;21(2):133-41
references: 10816374
references: Front Biosci. 2005 May 01;10:1754-62
references: 15769664
references: Minerva Pediatr. 2010 Jun;62(3 Suppl 1):51-4
references: 21089719
references: Thromb Diath Haemorrh. 1975 Nov 15;34(2):403-8
references: 1105875
references: J Biomed Biotechnol. 2012;2012:482096
references: 23118509
references: J Clin Invest. 2005 Sep;115(9):2499-507
references: 16138192
references: Infect Immun. 1999 Aug;67(8):3929-36
references: 10417158
references: Trends Microbiol. 2005 Feb;13(2):79-85
references: 15680767
references: Arch Dis Child Fetal Neonatal Ed. 2003 May;88(3):F179-84
references: 12719389
references: Microbiology (Reading). 2008 Mar;154(Pt 3):924-931
references: 18310038
references: PLoS Pathog. 2011 Jun;7(6):e1002082
references: 21731486
references: Microb Pathog. 2001 Jan;30(1):19-28
references: 11162182
references: Expert Rev Mol Med. 2008 Sep 22;10:e27
references: 18803886
references: J Clin Invest. 1999 Jan;103(1):81-7
references: 9884337
references: Microbes Infect. 2007 Sep;9(11):1276-84
references: 17890121
references: J Infect Dis. 2009 May 15;199(10):1479-87
references: 19392623
references: Lancet Infect Dis. 2010 Jan;10(1):32-42
references: 20129147
references: J Pediatr. 1985 May;106(5):717-22
references: 3889248
references: J Exp Med. 2010 Oct 25;207(11):2313-22
references: 20956545
references: Science. 2004 Aug 27;305(5688):1283-6
references: 15333838
references: J Neuroimmunol. 1997 Jun;76(1-2):81-90
references: 9184636
references: J Biomed Biotechnol. 2012;2012:272148
references: 23118502
references: Infect Immun. 1995 Jul;63(7):2478-84
references: 7790059
references: J Thromb Haemost. 2007 Jul;5 Suppl 1:24-31
references: 17635705
references: Science. 2007 Jan 26;315(5811):509-13
references: 17255510
references: Int J Parasitol. 2006 May 1;36(5):607-14
references: 16542662
references: Prog Neurobiol. 2010 Jun;91(2):130-9
references: 20026234
references: Cell. 1997 Jun 27;89(7):1111-9
references: 9215633
references: J Biol Chem. 2000 Jul 21;275(29):21856-61
references: 10806213
references: Infect Immun. 1997 Dec;65(12):5074-81
references: 9393798
references: Infect Immun. 2005 Feb;73(2):1014-22
references: 15664945
references: Curr Opin Microbiol. 2012 Feb;15(1):44-9
references: 22206860
references: J Biol Chem. 2010 Mar 5;285(10):7517-24
references: 20048164
references: Am J Physiol. 1992 Dec;263(6 Pt 2):F1112-8
references: 1481887
references: Microbes Infect. 2000 Aug;2(10):1237-44
references: 11008113
references: Mol Microbiol. 2004 Oct;54(1):23-31
references: 15458402
references: Nat Rev Microbiol. 2008 Aug;6(8):625-34
references: 18604221
references: J Clin Pathol Suppl (R Coll Pathol). 1980;14:41-7
references: 7000846
references: PLoS One. 2009 Jun 03;4(6):e5780
references: 19492051
references: Thromb Haemost. 2007 Sep;98(3):488-96
references: 17849036
references: J Bacteriol. 2007 Feb;189(4):1464-7
references: 17041051
references: Physiology (Bethesda). 2006 Aug;21:281-8
references: 16868317
references: J Clin Invest. 2003 Sep;112(5):736-44
references: 12952922
references: Infect Immun. 2001 Sep;69(9):5832-9
references: 11500461
references: Cell Microbiol. 2003 Apr;5(4):245-52
references: 12675682