Poxviruses and Pro-Resolving Lipids

痘病毒和促溶解脂质

• 批准号: 8808629
• 负责人: Christopher C Norbury
• 金额: $ 19.81万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-11-10 至 2016-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8808629
• 关键词: Acute; Anti-Inflammatory Agents; Anti-inflammatory; Antibody Response; Antiviral Agents; Arachidonate 15-Lipoxygenase; Arachidonic Acids; Area; Biology; CD4 Positive T Lymphocytes; CD59 Antigen; CD8B1 gene; Cells; Cessation of life; Chronic; Collaborations; Complex; Data; Dendritic Cells; Diet; Ectromelia; Enzymes; Family; Fatty Acids; Future; Goals; Healed; Health; Homeostasis; Human; Immune; Immune response; Immune system; Immunity; Immunocompromised Host; In Vitro; Individual; Infection; Infectious Ectromelia; Inflammation; Inflammatory; Interferon Type I; Interleukin-6; Knowledge; Laboratories; Lipids; Lipoxins; Liver; Lymph Node Tissue; Membrane; Modeling; Molluscum Contagiosum; Molluscum contagiosum virus; Monkeypox; Monkeypox virus; Mouse Pox Virus; Mus; Natural Killer Cells; Omega-3 Fatty Acids; Phenotype; Poxviridae; Poxviridae Infections; Predisposition; Process; Production; Proteins; Resolution; Risk; Role; Serpins; Skin; Smallpox; Somatic Cell; Spleen; Sterility; System; Systemic infection; Tissues; Vaccinia virus; Vertebral column; Viral; Viral Vaccines; Virus; Virus Activation; Virus Diseases; Work; adaptive immunity; base; cell type; cytokine; design; experience; healing; immune activation; immune function; immunopathology; in vivo; lipid mediator; macrophage; medical schools; novel; pathogen; prevent; programs; tissue regeneration; transmission process; vector

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.

描述（由申请人提供）：病毒已经进化到能够尽可能有效地感染宿主、繁殖并传播到另一个宿主。相比之下，受感染的宿主已经进化到能够在感染中存活下来，而不管病毒是否传播。病毒在传播之前会采取许多不同的方法在宿主中生存，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，以预防病毒引起的疾病。然而，过度旺盛的免疫反应可能会导致免疫病理学，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（以提供足够的传播机会）和宿主（以防止免疫病理学）来调节免疫反应，并且病毒和宿主通常使用类似的方法来实现这一目标。在本提案中，我们将研究促溶解脂质的作用，这些脂质是 omega-3 脂肪酸 15-脂氧合酶作用的产物，具有深远的抗炎作用。我们史无前例地发现，缺乏 15-脂氧合酶的小鼠容易受到 ectromelia 病毒的致命攻击，而 ectromelia 病毒是一种痘病毒，是小鼠的天然病原体，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，但通过猴痘病毒、骆驼痘和水牛痘传播给人类，全世界人类感染的风险不断增加。因此，这些研究对人类健康具有广泛的影响，包括这些感染、有效病毒疫苗载体的设计以及整个病毒感染的脂质调节。痘病毒还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，它已被证明可以改变受感染细胞中脂质的产生。在目标 1 中，我们将检查 ectromelia 感染导致促溶解脂质产生的变化，无论是在体外不同细胞类型中还是在感染过程中的体内。此外，我们将检查免疫调节蛋白 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-脂氧合酶的情况下对 ECTV 的先天性和适应性免疫反应的变化，以及 SPI-2 的作用如何改变这种变化。我们期望所产生的结果能够全面表征痘病毒感染如何改变体外和体内促溶解脂质的产生。我们预计从这些研究中获得的结果将构成未来 RO1 或 PO1 提案的基础，其中将检查促溶解脂质赋予细胞免受致命病毒攻击的存活的机制。