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: 8228056
• 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/8228056
• 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. PUBLIC HEALTH RELEVANCE: 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.

描述（由申请人提供）：凝血与纤维蛋白溶解之间的平衡不仅对于维持体内平衡至关重要，而且还可以对创伤和感染做出适当的反应。此外，还存在纤维蛋白沉积与炎症之间的紧密联系。然而，一些细菌病原体已开发出毒力策略来操纵宿主的血栓形成和纤维蛋白水解途径。革兰氏阴性细菌耶尔森氏菌瘟疫会引起疾病鼠疫，可以以三种不同的形式表现出来：泡泡性，败血症和肺炎。如果未经治疗，则Y. Pestis感染与高水平的发病率和死亡率有关，尤其是在将细菌引入肺部时。我们已经表明，细菌毒力因子PLA是纤溶酶原激活蛋白蛋白酶，对于Y. Pestis引起原发性肺炎鼠疫至关重要，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显着不同于其在泡沫鼠疫中的作用，因此PLA在肺中造成细菌的毒力的机制未知。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血块，增强纤维蛋白溶解，这被认为使细菌复制和扩散。此外，PLA使纤溶酶的主要抑制剂12-抗血压素失活。我们假设，通过激活纤溶酶并降解12-抗血压素，pestis使用PLA诱导高度纤维蛋白水解状态，从而改变了对感染的炎症反应，从而导致迅速发展和严重的肺炎的发展。我们建议确定Y. Pestis诱导的肺血栓形成的程度，血浆蛋白原和纤维蛋白原在控制肺炎鼠疫中所起的作用，PLA对PLA对凝血和纤维蛋白溶解的影响以及这些因素对原始pnepne Prag peremonic Plag perimonic Peremonic plag premonic plague promantic phemomonic plag的凝结状态的贡献。 公共卫生相关性：疾病瘟疫在人类历史过程中估计造成了2亿人死亡，并且在全球和美国仍然是公共卫生威胁。对耶尔森氏菌通过凝血和纤维蛋白解会导致原发性肺炎鼠疫的机制的理解对于开发针对该细菌的有效对策至关重要。该项目旨在在遗传和生化水平上阐明这些机制，并可能对了解其他细菌病原体如何影响感染过程中的血栓形成和纤维蛋白溶解有影响。