Poxviruses and Pro-Resolving Lipids

描述（由申请人提供）：病毒已进化为尽可能有效地感染宿主、繁殖并传播至另一宿主。相反，受感染的宿主已经进化到试图在感染中生存，而不管病毒的传播。病毒在传播之前采取许多不同的方法在宿主中存活，例如操纵宿主免疫反应以减少或阻止病毒的识别或清除。宿主免疫反应的任务是尽快清除病原体，防止病毒引起的疾病。然而，过度旺盛的免疫反应可能导致免疫病理学，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（以允许足够的传播机会）和宿主（以防止免疫病理学）来调节免疫应答，并且通常病毒和宿主使用类似的方法来实现该目标。在本提案中，我们将研究促分解脂质的作用，这些脂质是ω-3脂肪酸的15-脂氧合酶作用的产物，并且具有深刻的抗炎作用。我们已经取得了前所未有的发现，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，是小鼠的天然病原体，也是导致小鼠痘的原因。痘病毒是一个独特的病毒家族，尽管天花已被根除，但其通过猴痘病毒、骆驼痘和水牛痘传播给人类的作用，在世界范围内构成了不断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意义，无论是对于这些感染，对于有效的病毒疫苗载体的设计，还是对于病毒感染的脂质调节。痘病毒还已知编码许多改变免疫功能的调节蛋白，其中包括丝氨酸蛋白酶抑制剂SPI-2，其已显示改变受感染细胞中脂质的产生。在目的1中，我们将检查在不同细胞类型中的体外和在感染过程中的体内两种情况下，通过鼠痘感染改变促分解脂质的产生的变化。此外，我们将研究免疫调节蛋白SPI-2对体外和体内观察到的变化的影响。在目标2中，我们将研究在不存在15-脂氧合酶的情况下对ECTV的先天性和适应性免疫应答的变化，以及SPI-2的作用如何改变这种免疫应答。我们期望所产生的结果是一个全面的表征痘病毒感染如何改变生产的亲解决脂质在体外和体内。我们预计，从这些研究中获得的结果将形成未来的RO 1或PO 1建议的基础上，其中亲解决脂质赋予从致命的病毒挑战的生存机制进行检查。

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.