The balance between coagulation and fibrinolysis is essential not only to maintain homeostasis but also to enable an appropriate response to trauma and infection. In addition, there exists an intimate link between fibrin deposition and inflammation. Some bacterial pathogens, however, have developed virulence strategies to manipulate the host thrombotic and fibrinolytic pathways. The Gram-negative bacterium Yersinia pestis causes the disease plague, which can manifest in three distinct forms: bubonic, septicemic, and pneumonic. If untreated, Y. pestis infection is associated with high levels of morbidity and mortality, particularly when the bacteria are introduced into the lungs. We have shown that the bacterial virulence factor Pla, the plasminogen activator protease, is essential for Y. pestis to cause primary pneumonic plague and is required to induce a pro-inflammatory state in the lungs. Interestingly, the role of Pla during pneumonic plague appears to be significantly different that its role during bubonic plague, and therefore the mechanisms by which Pla contributes to the virulence of the bacterium in the lungs are unknown. In vitro, Pla converts host plasminogen to the active plasmin form. Plasmin breaks down fibrin clots, enhancing fibrinolysis, which is thought to allow the bacteria to replicate and spread. In addition, Pla inactivates 12-antiplasmin, the major inhibitor of plasmin. We hypothesize that, through the activation of plasmin and degradation of 12-antiplasmin, Y. pestis uses Pla induce a highly fibrinolytic state, which in turn alters the inflammatory response to the infection, resulting in the development of a rapidly progressing and severe pneumonia. We propose to determine the extent of pulmonary thrombosis induced by Y. pestis, the roles that plasminogen and fibrinogen play in the control of pneumonic plague, the effects that Pla has on coagulation and fibrinolysis, and the contribution of these factors to the development of the pro-inflammatory state that develops in the lungs during primary pneumonic plague.
The disease plague has caused an estimated 200 million deaths over the course of human history, and continues to be a public health threat, both worldwide and in the United States. An understanding of the mechanisms by which Yersinia pestis causes primary pneumonic plague through the alteration of coagulation and fibrinolysis is essential to developing effective countermeasures against this bacterium. This project is designed to elucidate those mechanisms at a genetic and biochemical level, and may have implications for understanding how other bacterial pathogens affect thrombosis and fibrinolysis during infection as well.
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|Eddy, Justin L; Schroeder, Jay A; Zimbler, Daniel L et al. (2015) Impact of the Pla protease substrate ?2-antiplasmin on the progression of primary pneumonic plague. Infect Immun 83:4837-47|
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