Submitted May 16, 2008
Accepted October 30, 2008
Proteolytic inactivation of tissue factor pathway inhibitor by bacterial omptins
Thomas H. Yun, Jessica E. Cott, Richard I. Tapping, James M. Slauch, and James H. Morrissey*
Biochemistry Department, College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, United States
Microbiology Department, College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, United States
* Corresponding author; email: jhmorris{at}illinois.edu.
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 in order 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 blots 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 in order to potentiate procoagulant responses to bacterial infection. This may contribute to the hemostatic imbalance in disseminated intravascular coagulation and other coagulopathies accompanying severe sepsis.
