Role of the Plasminogen Activator Protease during Pneumonic Plague

纤溶酶原激活物蛋白酶在肺鼠疫中的作用

• 批准号: 8605157
• 负责人: WYNDHAM W. LATHEM
• 金额: $ 38.13万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-15 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8605157
• 关键词: Aerosols; Affect; Afibrinogenemia; Anti-Inflammatory Agents; Anti-inflammatory; Antiplasmin; Bacillus (bacterium); Bacteria; Biochemical; Bite; Breathing; Bubonic Plague; Categories; Cessation of life; Coagulation Process; Data; Deposition; Development; Disease; Disease Progression; Environment; Enzyme Precursors; Equilibrium; Fibrin; Fibrinogen; Fibrinolysis; Fibrinolysis Pathway; Fleas; Genetic; Goals; Gram-Negative Bacteria; Homeostasis; Hour; Human; Immune response; In Vitro; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Integrin Binding; Leukocytes; Light; Link; Lung; Measures; Membrane; Modeling; Morbidity - disease rate; Mus; Pathogenesis; Pathway interactions; Pattern; Peptide Hydrolases; Pharmacia brand of estropipate; Phase; Plague; Plasmin; Plasmin Inhibitor; Plasminogen; Plasminogen Activator; Play; Pneumonia; Pneumonic Plague; Process; Public Health; Recording of previous events; Respiratory Tract Infections; Respiratory physiology; Role; Route; Site; Syndrome; Thrombosis; Trauma; United States; Virulence; Virulence Factors; Yersinia pestis; design; macrophage; mortality; mouse model; neutrophil; pathogen; public health relevance; respiratory; response; vaccine development

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.

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，而且对创伤和感染的适当反应也至关重要。此外，纤维蛋白沉积与炎症之间存在密切联系。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维蛋白溶解途径。革兰氏阴性菌鼠疫耶尔森氏菌引起的疾病鼠疫，可以表现为三种不同的形式：腺鼠疫，败血症和肺炎。如果不治疗，Y.鼠疫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，纤溶酶原激活蛋白酶，是Y。鼠疫杆菌引起原发性肺鼠疫，并需要在肺中诱导促炎状态。有趣的是，在肺鼠疫期间，Pla的作用似乎与其在腺鼠疫期间的作用显著不同，因此Pla有助于肺中细菌毒力的机制尚不清楚。在体外，Pla将宿主纤溶酶原转化为活性纤溶酶形式。纤溶酶分解纤维蛋白凝块，增强纤维蛋白溶解，这被认为是允许细菌复制和传播。此外，PLA使纤溶酶的主要抑制剂12-抗纤溶酶失活。我们推测，通过激活纤溶酶和降解12-抗纤溶酶，Y。鼠疫杆菌使用Pla诱导高度纤维蛋白溶解状态，这反过来又改变了对感染的炎症反应，导致迅速进展和严重肺炎的发展。我们建议确定由Y.鼠疫的作用，纤溶酶原和纤维蛋白原在控制肺鼠疫中发挥的作用，Pla对凝血和纤维蛋白溶解的影响，以及这些因素对原发性肺鼠疫期间肺中发生的促炎状态的发展的贡献。