Modulation of adenovirus pathogenesis by prostaglandin E2

描述（由申请方提供）：腺病毒是呼吸道感染的常见原因。腺病毒感染的综合征范围从轻度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面临腺病毒感染的发病率和死亡率大大增加的风险。腺病毒引起的肺部炎症起保护作用，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，导致长期残留的肺部疾病。前列腺素E2（PGE 2）是一种脂质衍生的介质，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发挥多种作用。PGE 2具有多种免疫调节功能，协调免疫反应，保护免受病原体的侵害，同时抑制炎症，以限制对宿主的任何持久损害。另一方面，在骨髓移植（BMT）的小鼠模型中，过量的PGE 2产生已显示导致免疫抑制状态，其增加了移植宿主对细菌感染的易感性。 由于腺病毒严格的种属特异性，对腺病毒致病机制的研究受到限制。因此，很少有人知道PGE 2是如何刺激腺病毒感染，以及PGE 2是否调节腺病毒的发病机制。小鼠腺病毒1型（MAV-1）是研究腺病毒在其天然宿主中致病机制的一个极好的模型系统。该提案使用MAV-1研究PGE 2和腺病毒感染之间的相互作用，表征PGE 2在感染腺病毒的免疫活性宿主中的作用，并定义BMT后PGE 2过量产生导致免疫功能障碍和增强腺病毒疾病的机制。使用体外和体内方法的组合，本提案中概述的研究测试了以下假设：a）PGE 2是调节炎症反应的重要因子，其有助于免疫活性宿主中急性腺病毒呼吸道感染的发病机制，但B）BMT诱导的PGE 2产生增加宿主对腺病毒的易感性。这些研究将提供关于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基于调节PGE 2产生的药物的抗病毒治疗策略的发展，其中一些已经被批准用于其他适应症。由于用于治疗腺病毒感染的药物在数量和疗效上都是有限的，诸如此类的新策略将是腺病毒感染患者护理的重要补充。 公共卫生相关性：腺病毒感染可导致大量发病率和死亡率，特别是在免疫功能低下的患者人群中。这项工作的结果将提供有关前列腺素E2在宿主免疫功能和腺病毒感染之间相互作用的详细信息。我们预计，我们的研究将有助于开发基于调节前列腺素产生的药物的抗病毒治疗策略。

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. PUBLIC HEALTH RELEVANCE: Adenovirus infections cause substantial morbidity and mortality, particularly in immunocompromised patient populations. The results of this work will provide detailed information about the role of prostaglandin E2 in interactions between host immune function and adenovirus infection. We anticipate that our research will contribute to the development of antiviral treatment strategies based on drugs that modulate prostaglandin production.