title: Fibrinolytic and coagulative activities of Yersinia pestis.
abstract: The outer membrane protease Pla belongs to the omptin protease family spread by horizontal gene transfer into Gram-negative bacteria that infect animals or plants. Pla has adapted to support the life style of the plague bacterium Yersinia pestis. Pla has a β-barrel fold with 10 membrane-spanning β strands and five surface loops, and the barrel surface contains bound lipopolysaccharide (LPS) that is critical for the conformation and the activity of Pla. The biological activity of Pla is influenced by the structure of the surface loops around the active site groove and by temperature-induced LPS modifications. Several of the putative virulence-related functions documented for Pla in vitro address control of the human hemostatic system, i.e., coagulation and fibrinolysis. Pla activates human plasminogen to the serine protease plasmin and activates the physiological plasminogen activator urokinase. Pla also inactivates the protease inhibitors alpha-2-antiplasmin and plasminogen activator inhibitor 1 (PAI-1) and prevents the activation of thrombin-activatable fibrinolysis inhibitor (TAFI). These functions enhance uncontrolled fibrinolysis which is thought to improve Y. pestis dissemination and survival in the mammalian host, and lowered fibrin(ogen) deposition has indeed been observed in mice infected with Pla-positive Y. pestis. However, Pla also inactivates an anticoagulant, the tissue factor (TF) pathway inhibitor, which should increase fibrin formation and clotting. Thus, Pla and Y. pestis have complex interactions with the hemostatic system. Y. pestis modifies its LPS upon transfer to the mammalian host and we hypothesize that the contrasting biological activities of Pla in coagulation and fibrinolysis are influenced by LPS changes during infection.
authors.affiliation: General Microbiology, Department of Biosciences, University of Helsinki Helsinki, Finland. timo.korhonen@helsinki.fi
authors.forename: Timo K
authors.initials: TK
authors.lastname: Korhonen
authors.forename: Johanna
authors.initials: J
authors.lastname: Haiko
authors.forename: Liisa
authors.initials: L
authors.lastname: Laakkonen
authors.forename: Hanna M
authors.initials: HM
authors.lastname: Järvinen
authors.forename: Benita
authors.initials: B
authors.lastname: Westerlund-Wikström
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D001777:Blood Coagulation; D004731:Endotoxins / Q000378:metabolism; D005342:Fibrinolysis; D006801:Humans; D008070:Lipopolysaccharides / Q000378:metabolism; D051379:Mice; D010960:Plasminogen Activators / Q000378:metabolism*; D037521:Virulence Factors / Q000378:metabolism*; D015010:Yersinia pestis / Q000201:enzymology* / Q000472:pathogenicity*
chemical_list: D001426:Bacterial Proteins; D004731:Endotoxins; D008070:Lipopolysaccharides; D037521:Virulence Factors; C078140:Pla protease, Yersinia pestis; D010960:Plasminogen Activators
keywords: Yersinia pestis; coagulation; fibrinolysis; hemostasis; plague; plasminogen; proteolysis
references.citation: Mol Microbiol. 2004 Jan;51(1):215-25
references.pmid: 14651623
references.citation: PLoS One. 2008 Feb 27;3(2):e1688
references.pmid: 18301765
references.citation: Thromb Res. 2006;118(2):205-12
references.pmid: 16009400
references.citation: J Thromb Haemost. 2007 Jul;5 Suppl 1:24-31
references.pmid: 17635705
references.citation: Infect Immun. 2007 Jan;75(1):429-42
references.pmid: 17074849
references.citation: Biochem J. 2010 May 27;428(3):473-82
references.pmid: 20337595
references.citation: Adv Exp Med Biol. 2012;954:253-60
references.pmid: 22782771
references.citation: Eur J Biochem. 2000 Feb;267(3):885-93
references.pmid: 10651827
references.citation: Structure. 2000 Jun 15;8(6):585-92
references.pmid: 10873859
references.citation: J Bacteriol. 2009 Aug;191(15):4758-66
references.pmid: 19465664
references.citation: Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11766-71
references.pmid: 16864791
references.citation: FEMS Microbiol Lett. 2001 Apr 13;197(2):229-33
references.pmid: 11313139
references.citation: J Bacteriol. 2010 Sep;192(18):4553-61
references.pmid: 20639337
references.citation: J Thromb Haemost. 2005 Jan;3(1):35-45
references.pmid: 15634264
references.citation: J Korean Med Sci. 1997 Feb;12(1):23-31
references.pmid: 9142656
references.citation: Thromb Res. 2012 Oct;130(4):576-85
references.pmid: 22801256
references.citation: FEMS Immunol Med Microbiol. 2011 Jul;62(2):173-81
references.pmid: 21395696
references.citation: Cell Microbiol. 2005 Apr;7(4):529-38
references.pmid: 15760453
references.citation: Thromb Res. 2012 Mar;129(3):290-5
references.pmid: 22061311
references.citation: Infect Immun. 2010 Dec;78(12):5086-98
references.pmid: 20876291
references.citation: Science. 2007 Jan 26;315(5811):509-13
references.pmid: 17255510
references.citation: Biochemistry. 2005 Feb 8;44(5):1731-43
references.pmid: 15683257
references.citation: Mol Microbiol. 2000 Jul;37(2):316-30
references.pmid: 10931327
references.citation: Mol Microbiol. 2001 Jun;40(5):1097-111
references.pmid: 11401715
references.citation: Microbiol Immunol. 2002;46(3):225-30
references.pmid: 12008933
references.citation: J Immunol. 2011 Aug 15;187(4):1866-76
references.pmid: 21724997
references.citation: J Bacteriol. 2010 Mar;192(6):1685-99
references.pmid: 20061468
references.citation: Innate Immun. 2009 Apr;15(2):67-80
references.pmid: 19318417
references.citation: Blood. 2007 Feb 15;109(4):1593-601
references.pmid: 17032919
references.citation: Biochem Biophys Res Commun. 2011 Oct 14;414(1):67-72
references.pmid: 21945446
references.citation: J Bacteriol. 2005 Dec;187(23):8172-80
references.pmid: 16291690
references.citation: Bioorg Med Chem Lett. 2008 Jan 1;18(1):427-31
references.pmid: 17981463
references.citation: EMBO J. 2001 Sep 17;20(18):5033-9
references.pmid: 11566868
references.citation: Thromb Haemost. 2013 Feb;109(2):309-18
references.pmid: 23238745
references.citation: Blood. 2009 Jan 29;113(5):1139-48
references.pmid: 18988866
references.citation: J Bacteriol. 2007 Jan;189(2):522-30
references.pmid: 17085556
references.citation: Science. 1992 Nov 6;258(5084):1004-7
references.pmid: 1439793
references.citation: J Biol Chem. 2012 Jul 6;287(28):23971-6
references.pmid: 22645135
references.citation: J Infect Dis. 1999 Jul;180(1):176-86
references.pmid: 10353876
references.citation: Biochemistry. 2001 Feb 13;40(6):1694-701
references.pmid: 11327829
references.citation: Cell Mol Life Sci. 2011 Mar;68(5):785-801
references.pmid: 21136135
references.citation: J Cell Mol Med. 2009 Oct;13(10):4146-53
references.pmid: 19725923
references.citation: J Thromb Haemost. 2011 Oct;9(10):2020-8
references.pmid: 21848642
references.citation: Structure. 2010 Jul 14;18(7):809-18
references.pmid: 20637417
references.citation: Infect Immun. 2010 Jun;78(6):2644-52
references.pmid: 20368351
references.citation: Biochem J. 2008 Feb 15;410(1):157-65
references.pmid: 17973626
references.citation: Biochemistry. 2002 May 28;41(21):6688-96
references.pmid: 12022872
references.citation: Proc Natl Acad Sci U S A. 2011 Jan 25;108(4):1639-44
references.pmid: 21220342
references.citation: Anesthesiology. 2007 Feb;106(2):252-61
references.pmid: 17264718
references.citation: J Bacteriol. 2004 Sep;186(18):6298-305
references.pmid: 15342600
references.citation: BMC Evol Biol. 2011 Feb 11;11:43
references.pmid: 21310089
references.citation: Int J Biochem Cell Biol. 2007;39(4):690-4
references.pmid: 17118695
references.citation: Blood Coagul Fibrinolysis. 2011 Sep;22(6):480-6
references.pmid: 21577093
references.citation: Int J Med Microbiol. 2008 Apr;298(3-4):263-78
references.pmid: 17888724
references.citation: Eur Biophys J. 2005 Feb;34(1):28-41
references.pmid: 15241571
references.citation: Infect Immun. 2002 Aug;70(8):4092-8
references.pmid: 12117916
references.citation: Physiology (Bethesda). 2006 Aug;21:281-8
references.pmid: 16868317
references.citation: J Wildl Dis. 2011 Oct;47(4):968-73
references.pmid: 22102668
references.citation: Thorax. 2011 Sep;66(9):788-96
references.pmid: 21768189
references.citation: DNA Res. 2004 Jun 30;11(3):179-97
references.pmid: 15368893
references.citation: Cell Mol Life Sci. 2004 Nov;61(22):2840-58
references.pmid: 15558213
references.citation: Infect Immun. 2008 Apr;76(4):1456-64
references.pmid: 18227173
references.citation: Basic Appl Histochem. 1986;30(3):333-41
references.pmid: 3539084
references.citation: J Bacteriol. 2004 Sep;186(17):5919-25
references.pmid: 15317797
references.citation: FEBS Lett. 2001 Sep 21;505(3):426-30
references.pmid: 11576541
references.citation: Eur J Biochem. 2002 Mar;269(6):1746-52
references.pmid: 11895445
references.citation: Mol Microbiol. 2013 Aug;89(3):507-17
references.pmid: 23763588
references.citation: J Thromb Haemost. 2010 Oct;8(10):2232-40
references.pmid: 20704647
references.citation: J Clin Invest. 2004 Jun;113(11):1596-606
references.pmid: 15173886
references.citation: J Immunol. 2013 Apr 15;190(8):4149-61
references.pmid: 23487423
references.citation: Trends Microbiol. 2005 Feb;13(2):79-85
references.pmid: 15680767
references.citation: Nat Immunol. 2006 Oct;7(10):1066-73
references.pmid: 16980981
references.citation: J Basic Microbiol. 2009 Feb;49(1):92-9
references.pmid: 18759226
references.citation: Mol Microbiol. 2013 Jul;89(2):276-87
references.pmid: 23701256