Modulation of adenovirus pathogenesis by prostaglandin E2

前列腺素 E2 对腺病毒发病机制的调节

• 批准号: 8451349
• 负责人: Jason Brice Weinberg
• 金额: $ 35.52万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8451349
• 关键词: Acute; Adenovirus Infections; Adenoviruses; Affect; Alveolar Macrophages; Antiviral Agents; Arachidonic Acids; Bacterial Infections; Biological Models; Bone Marrow Transplantation; Cyclic AMP; Development; Dinoprostone; Disease; Drug usage; Gene Expression; Hematopoietic; Human Adenovirus Infections; Human Adenoviruses; Immune; Immune System Diseases; Immune response; Immunocompetent; Immunocompromised Host; In Vitro; Infection; Inflammation; Inflammatory Response; Laboratory Animals; Life; Lipids; Lung; Lung diseases; Mediator of activation protein; Membrane; Morbidity - disease rate; Mus; Pathogenesis; Patient Care; Pharmaceutical Preparations; Phospholipase A2; Pneumonia; Predisposition; Production; Prostaglandin H2; Prostaglandin Production; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Research; Residual state; Respiratory Tract Infections; Risk; Role; Species Specificity; Syndrome; Syngeneic Bone Marrow Transplantation; System; Testing; Transplantation; Upper Respiratory Infections; Viral Genes; Virus; Work; base; human WFDC2 protein; immune function; immunosuppressed; in vivo; mortality; mouse model; novel strategies; pathogen; patient population; public health relevance; receptor; reconstitution; response; treatment strategy

DESCRIPTION (provided by applicant): Adenoviruses are common causes of respiratory infections. Adenovirus infections present with syndromes that range from mild upper respiratory tract infections to more severe, sometimes life-threatening manifestations. Immunocompromised patients are at risk for greatly increased morbidity and mortality from adenovirus infections. Adenovirus-induced pulmonary inflammation serves a protective role, aiding in the clearance of virus from the lungs. Adenovirus-induced inflammation also can be harmful; leading to damage that contributes to long-term residual lung disease. Prostaglandin E2 (PGE2) is a lipid-derived mediator that exerts a variety of effects on host immune function, in many cases via receptors that increase intracellular cAMP levels. PGE2 serves a variety of immunomodulatory functions, coordinating immune responses that protect from a pathogen while dampening inflammation in an effort to limit any lasting damage to the host. On the other hand, exaggerated PGE2 production in a mouse model of bone marrow transplantation (BMT) has been shown to result in an immunosuppressed state that increases the transplanted host's susceptibility to bacterial infection. Studies of human adenovirus pathogenesis are limited by the strict species specificity of the adenoviruses. As a consequence, very little is known about how PGE2 is stimulated by adenovirus infection and whether PGE2 modulates adenovirus pathogenesis. Mouse adenovirus type 1 (MAV-1) serves as an excellent model system to study the pathogenesis of an adenovirus in its natural host. This proposal uses MAV-1 to study interactions between PGE2 and adenovirus infection, characterizing the role of PGE2 in an immunocompetent host infected with an adenovirus and defining mechanisms by which PGE2 overproduction following BMT tips the scale towards immune dysfunction and enhanced adenovirus disease. Using a combination of in vitro and in vivo approaches, the research outlined in this proposal tests the hypothesis that a) PGE2 is an important factor regulating inflammatory responses that contribute to the pathogenesis of acute adenovirus respiratory infection in an immunocompetent host, but b) exaggerated PGE2 production induced by BMT increases host susceptibility to an adenovirus. These studies will provide detailed information regarding host immune function and adenovirus pathogenesis. In addition, we anticipate that the results of our work will contribute to the development of antiviral treatment strategies based on drugs that modulate PGE2 production, some of which are already approved for other indications. Because drugs used to treat adenovirus infections are limited in number and efficacy, novel strategies such as these will be important additions to the care of patients infected with adenoviruses.

描述（由申请人提供）：腺病毒是呼吸道感染的常见原因。腺病毒感染会出现各种症状，从轻微的上呼吸道感染到更严重的、有时危及生命的表现。免疫功能低下的患者因腺病毒感染而面临发病率和死亡率大大增加的风险。腺病毒引起的肺部炎症具有保护作用，有助于从肺部清除病毒。腺病毒引起的炎症也可能是有害的。导致损害，导致长期残留肺部疾病。前列腺素 E2 (PGE2) 是一种脂质衍生介质，在许多情况下通过增加细胞内 cAMP 水平的受体对宿主免疫功能产生多种影响。 PGE2 具有多种免疫调节功能，协调免疫反应，抵御病原体，同时抑制炎症，以限制对宿主的任何持久损害。另一方面，骨髓移植 (BMT) 小鼠模型中 PGE2 的过量产生已被证明会导致免疫抑制状态，从而增加移植宿主对细菌感染的易感性。 人类腺病毒发病机制的研究受到腺病毒严格的物种特异性的限制。因此，人们对腺病毒感染如何刺激 PGE2 以及 PGE2 是否调节腺病毒发病机制知之甚少。小鼠腺病毒 1 型 (MAV-1) 是研究腺病毒在其自然宿主中发病机制的优秀模型系统。该提案使用 MAV-1 研究 PGE2 和腺病毒感染之间的相互作用，描述 PGE2 在感染腺病毒的免疫功能正常宿主中的作用，并确定 BMT 后 PGE2 过量产生导致免疫功能障碍和增强腺病毒疾病的机制。本提案中概述的研究结合体外和体内方法，检验了以下假设：a) PGE2 是调节炎症反应的重要因素，有助于免疫功能正常宿主中急性腺病毒呼吸道感染的发病机制，但 b) 夸大了BMT 诱导的 PGE2 产生增加了宿主对腺病毒的易感性。这些研究将提供有关宿主免疫功能和腺病毒发病机制的详细信息。此外，我们预计我们的工作结果将有助于开发基于调节 PGE2 产生的药物的抗病毒治疗策略，其中一些药物已被批准用于其他适应症。由于用于治疗腺病毒感染的药物数量和疗效有限，因此诸如此类的新策略将成为腺病毒感染患者护理的重要补充。