Role of the Plasminogen Activator Protease during Pneumonic Plague

描述（由申请人提供）：凝血和纤溶之间的平衡不仅对维持体内平衡至关重要，而且对创伤和感染也能做出适当的反应。此外，纤维蛋白沉积与炎症之间存在着密切的联系。然而，一些细菌病原体已经发展出毒力策略来操纵宿主血栓形成和纤溶途径。革兰氏阴性菌鼠疫耶尔森氏菌引起鼠疫，可表现为三种不同的形式：腺鼠疫、败血症和肺炎。如果不加以治疗，鼠疫杆菌感染与高发病率和死亡率有关，特别是当细菌进入肺部时。我们已经证明，细菌毒力因子Pla，即纤溶酶原激活物蛋白酶，对于鼠疫杆菌引起原发性肺鼠疫是必不可少的，并且需要在肺部诱导促炎状态。有趣的是，Pla在肺鼠疫中的作用似乎与在腺鼠疫中的作用有显著不同，因此Pla对肺部细菌毒力的作用机制尚不清楚。在体外，Pla将宿主纤溶酶原转化为活性纤溶酶形式。纤溶蛋白分解纤维蛋白凝块，增强纤维蛋白溶解，这被认为是允许细菌复制和传播。此外，聚乳酸还能使12-抗纤溶酶失活，这是纤溶酶的主要抑制剂。我们推测，通过激活纤溶蛋白和降解12-抗纤溶蛋白，鼠疫菌利用Pla诱导高度纤溶状态，进而改变对感染的炎症反应，导致快速进展和严重肺炎的发展。我们拟确定鼠疫杆菌引起肺血栓形成的程度，纤溶酶原和纤维蛋白原在肺鼠疫控制中的作用，Pla对凝血和纤维蛋白溶解的影响，以及这些因素在原发性肺鼠疫期间肺促炎状态发展中的作用。

DESCRIPTION (provided by applicant): 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.