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

基本信息

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
项目类别：
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

项目摘要

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于维持体内平衡至关重要，而且对于能够对创伤和感染做出适当的反应也是至关重要的。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溶途径。革兰氏阴性菌鼠疫耶尔森氏菌引起鼠疫，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，鼠疫耶尔森氏菌感染会导致高发病率和死亡率，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）对于鼠疫耶尔森氏菌引起原发性肺鼠疫至关重要，并且是诱导肺部促炎症状态所必需的。有趣的是，Pla 在肺鼠疫中的作用似乎与其在黑死病中的作用显着不同，因此 Pla 导致肺部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，这被认为可以使细菌复制和传播。此外，Pla 还能灭活 12-抗纤溶酶（纤溶酶的主要抑制剂）。我们假设，通过激活纤溶酶和降解 12-抗纤溶酶，鼠疫耶尔森氏菌利用 Pla 诱导高度纤溶状态，从而改变对感染的炎症反应，导致快速进展的严重肺炎的发展。我们建议确定鼠疫耶尔森氏菌引起的肺血栓形成的程度、纤溶酶原和纤维蛋白原在控制肺鼠疫中的作用、Pla 对凝血和纤维蛋白溶解的影响，以及这些因素对肺血栓形成的贡献。原发性肺鼠疫期间肺部形成的促炎状态。