Proteolytic inactivation of tissue factor pathway inhibitor by bacterial omptins

Thomas H. Yun, Jessica E. Cott, Richard I. Tapping, James M. Slauch, James H. Morrissey

Research output: Contribution to journalArticle

Abstract

The immune response to infection includes activation of the blood clotting system, leading to extravascular fibrin deposition to limit the spread of invasive microorganisms. Some bacteria have evolved mechanisms to counteract this host response. Pla, a member of the omptin family of Gram-negative bacterial proteases, promotes the invasiveness of the plague bacterium, Yersinia pestis, by activating plasminogen to plasmin to digest fibrin.We now show that the endogenous anticoagulant tissue factor pathway inhibitor (TFPI) is also highly sensitive to proteolysis by Pla and its orthologs OmpT in Escherichia coli and PgtE in Salmonella enterica serovar Typhimurium. Using gene deletions, we demonstrate that bacterial inactivation of TFPI requires omptin expression. TFPI inactivation is mediated by proteolysis since Western blot analysis showed that TFPI cleavage correlated with loss of anticoagulant function in clotting assays. Rates of TFPI inactivation were much higher than rates of plasminogen activation, indicating that TFPI is a better substrate for omptins. We hypothesize that TFPI has evolved sensitivity to proteolytic inactivation by bacterial omptins to potentiate procoagulant responses to bacterial infection. This may contribute to the hemostatic imbalance in disseminated intravascular coagulation and other coagulopathies accompanying severe sepsis.

Original languageEnglish (US)
Pages (from-to)1139-1148
Number of pages10
JournalBlood
Volume113
Issue number5
DOIs
StatePublished - Jan 29 2009

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Proteolysis
Plasminogen
Fibrin
Anticoagulants
Bacteria
Chemical activation
Yersinia pestis
Salmonella
Salmonella enterica
Plague
Disseminated Intravascular Coagulation
Fibrinolysin
Gene Deletion
Blood Coagulation
Hemostatics
omptin outer membrane protease
lipoprotein-associated coagulation inhibitor
Coagulation
Bacterial Infections
Microorganisms

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Proteolytic inactivation of tissue factor pathway inhibitor by bacterial omptins. / Yun, Thomas H.; Cott, Jessica E.; Tapping, Richard I.; Slauch, James M.; Morrissey, James H.

In: Blood, Vol. 113, No. 5, 29.01.2009, p. 1139-1148.

Research output: Contribution to journalArticle

Yun, Thomas H. ; Cott, Jessica E. ; Tapping, Richard I. ; Slauch, James M. ; Morrissey, James H. / Proteolytic inactivation of tissue factor pathway inhibitor by bacterial omptins. In: Blood. 2009 ; Vol. 113, No. 5. pp. 1139-1148.
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