Modulation of adenovirus pathogenesis by prostaglandin E2

描述（由申请人提供）：腺病毒是呼吸道感染的常见原因。腺病毒感染的症状范围从轻微的上呼吸道感染到更严重的，有时危及生命的症状。免疫功能低下的患者有因腺病毒感染而大大增加发病率和死亡率的危险。腺病毒引起的肺部炎症起到保护作用，帮助清除肺部的病毒。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）是一种脂质来源的介质，对宿主免疫功能产生多种影响，在许多情况下通过受体增加细胞内cAMP水平。PGE2具有多种免疫调节功能，协调免疫反应，保护宿主免受病原体侵害，同时抑制炎症，以限制对宿主的任何持久损害。另一方面，骨髓移植（BMT）小鼠模型中过度的PGE2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种特异性的限制。因此，对于腺病毒感染如何刺激PGE2以及PGE2是否调节腺病毒的发病机制知之甚少。小鼠腺病毒1型（MAV-1）是研究腺病毒在其自然宿主中的发病机制的一个很好的模型系统。本研究利用MAV-1研究PGE2与腺病毒感染之间的相互作用，表征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腺病毒疾病加重的机制。采用体外和体内结合的方法，本研究概述了以下假设：a) PGE2是调节炎症反应的重要因素，有助于免疫功能正常的宿主急性腺病毒呼吸道感染的发病机制，但b) BMT诱导的PGE2的过量产生增加了宿主对腺病毒的易感性。这些研究将提供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PGE2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，因此诸如此类的新策略将是对腺病毒感染患者护理的重要补充。

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.