Poxviruses and Pro-Resolving Lipids

描述(申请人提供)：病毒已经进化到感染一个宿主，尽可能有效地传播和传播到另一个宿主。相比之下，受感染的宿主已经进化到试图在感染中幸存下来，而不考虑病毒的传播。病毒在传播之前采取许多不同的方法在宿主中生存，例如操纵宿主的免疫反应以减少或阻止对病毒的识别或清除。宿主免疫应答的任务是尽快清除病原体，预防病毒引起的疾病。然而，过度活跃的免疫反应可能导致免疫病理，可能导致宿主死亡，这是进化的死胡同。因此，这是双方的目标 病毒(允许足够的传播机会)和宿主(防止免疫病理)缓和免疫反应，通常病毒和宿主使用类似的方法来实现这一目标。在这项建议中，我们将研究促分解脂的作用，这些脂是omega-3脂肪酸15-脂氧合酶作用的产物，具有深刻的抗炎作用。我们做出了前所未有的发现，缺乏15-脂氧合酶的小鼠容易受到鼠痘病毒的致命攻击，这是一种痘病毒，是老鼠的自然病原体，也是鼠痘的原因。痘病毒是一个独特的病毒家族，尽管天花已被根除，但由于猴痘病毒、骆驼痘和水痘传播给人类，这种病毒在世界范围内构成了日益增加的人类感染风险。因此，这些研究对人类健康具有广泛的影响，无论是对于这些感染，还是对于有效的病毒载体的设计，以及对整个病毒感染的脂质调节都是如此。众所周知，痘病毒还编码许多能改变免疫功能的调节蛋白，其中包括丝氨酸SPI-2，它已被证明能改变受感染细胞中脂质的产生。在目标1中，我们将检查不同细胞类型的体外和体内感染病程中，皮质炎感染后促分解脂类的产生的变化。此外，我们还将检测免疫调节蛋白SPI-2对体外和体内观察到的变化的影响。在目标2中，我们将研究在没有15-脂氧合酶的情况下ECTV的先天和获得性免疫反应的变化，以及SPI-2的作用是如何改变这种变化的。我们期望所产生的结果是对痘病毒感染如何在体外和体内改变促分解脂质的产生的全面表征。我们期望从这些研究中获得的结果将成为未来RO1或PO1建议的基础，在该建议中，检测促分解脂质使患者在致死性病毒攻击中存活的机制。

DESCRIPTION (provided by applicant): Viruses have evolved to infect a host, propagate and be transmitted to another host as efficiently as possible. In contrast, an infected host has evolved to try to survive infection, irrespective of transmission of the virus. Viruses take many different approaches to survival in a host prior to transmission, such as manipulating the host immune response to reduce or prevent recognition or clearance of the virus. The task of the host immune response is to clear the pathogen as quickly as possible to prevent virus-induced disease. However, an over exuberant immune response can cause immunopathology, potentially leading to death of the host, an evolutionary dead end. Therefore it is the aim of both the virus (to allow sufficient opportunity for transmission) and the host (to prevent immunopathology) to moderate the immune response and often virus and host use similar approaches to achieve this goal. In this proposal we will examine the role of pro-resolving lipids that are products of 15-lipoxygenase action of omega-3 fatty acids, and which have a profound anti-inflammatory action. We have made the unprecedented finding that mice lacking 15-lipoxygenase are susceptible to lethal challenge with ectromelia virus, a poxvirus that is a natural pathogen of mice and is the cause of mousepox. Poxviruses are a unique family of viruses that, despite the eradication of smallpox, constitute an ever- increasing risk of human infection worldwide via the action of monkeypoxvirus, camelpox and buffalopox transmission to humans. Therefore these studies have broad implications for human health, both for these infections, for the design of effective viral vacine vectors, and for lipid moderation of virus infections as a whole. Poxviruses are also known to encode many modulatory proteins that alter immune function, among them the serpin SPI-2, that has been shown to alter production of lipids in infected cells. In Aim 1 we will examine the changes in the production of pro-resolving lipids is changed by ectromelia infection, both in vitro in different cell types and in vivo over te course of infection. In addition, we will examine the effect of the immunomodulatory protein SPI-2 upon the changes observed in vitro and in vivo. In Aim 2 we will examine the changes in the innate and adaptive immune response to ECTV in the absence of 15-lipoxygenase, and how this is changed by the action of SPI-2. We expect the results produced to be a comprehensive characterization of how poxvirus infection changes the production of pro-resolving lipids both in vitro and in vivo. We anticipate that the results gained from these studies will form the basis of future RO1 or PO1 proposal in which the mechanisms by which pro-resolving lipids confer survival from lethal viral challenge are examined.