Interferon-independent STAT1-mediated protective antiviral immunity

不依赖干扰素的STAT1介导的保护性抗病毒免疫

• 批准号: 9378819
• 负责人: Christopher C Norbury
• 金额: $ 19.34万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-05 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9378819
• 关键词: Ablation; Address; Animals; Antiviral Agents; Antiviral Response; B-Lymphocytes; C-KIT Gene; Cause of Death; Cell Surface Receptors; Cell physiology; Cell surface; Cells; Cessation of life; Cidofovir; Data; Dendritic Cells; Dermal; Dermis; Development; Event; Failure; Family; Future; Gene Expression; Gene Targeting; Genes; Goals; Immune; Immune response; Immune system; Immunity; Immunize; In Vitro; Individual; Infection; Infectious Skin Diseases; Insect Bites; Interferon Receptor; Interferon-alpha; Interferons; Investigation; Janus kinase; Knowledge; Mediating; Mediator of activation protein; Modeling; Molluscum Contagiosum; Molluscum contagiosum virus; Morbidity - disease rate; Mus; Myxoma virus; Natural Immunity; Natural Killer Cells; Nuclear Translocation; Oryctolagus cuniculus; Pathogenesis; Pathway interactions; Patients; Peripheral; Phenotype; Phosphorylation; Population; Poxviridae; Poxviridae Infections; Predisposition; Process; Protein Family; Proteins; Proto-Oncogene Protein c-kit; Publishing; Receptor Gene; Receptor Signaling; Recruitment Activity; Resistance; Role; Route; STAT protein; STAT1 gene; STAT2 gene; STAT3 gene; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Skin; Smallpox; Smallpox Vaccine; Species Specificity; Surface; System; Systemic disease; T-Lymphocyte; Toll-like receptors; Up-Regulation; Vaccines; Vaccinia virus; Vertebral column; Viral; Viral Vaccines; Virion; Virus; Virus Diseases; Virus Replication; Wild Type Mouse; adaptive immune response; adaptive immunity; antiviral immunity; cell type; cytokine; in vivo; killings; macrophage; monocyte; mortality; novel; prevent; programs; receptor; receptor binding; response; vector vaccine

Viral skin infections are a significant cause of morbidity and mortality, with millions of individuals infected worldwide with the poxvirus molluscum contagiosum virus (MCV). The related poxvirus Vaccinia virus (VACV) was used to immunize hundreds of millions of people during the smallpox eradication program, and remains a backbone of the many widely used viral vaccine vectors. The goal of the immune system is to restrict virus spread until an adaptive immune response can be mounted that will clear the virus. Interferons (IFN) are a family of protein cytokines that upregulate IFN stimulated genes (ISGs) to restrict virus replication and spread and also activate the immune response via recruitment and activation of innate and effector immune cell populations. The IFN family consists of Type I, II and III, each using separate receptors. All IFN receptors signal through the Janus kinase (JAK)/ Signal Transducer and Activator of Transcription (STAT) pathway. STAT1 signals via interactions with a number of other STAT proteins to transduce signals after receptor binding of IFNs. After IFN receptor signaling, STAT1 is phosphorylated and subsequent nuclear translocation leads to activation of a large number of ISGs. Deletion of STAT1 can dramatically reduce the immune response to IFN in vitro and in vivo, and mice lacking STAT1 often succumb to systemic challenge with virus, including VACV. Because of the tight linkage of IFN signaling and STAT1, the lethal phenotype of STAT1-deficient mice upon virus challenge is most often assumed to be due to lack of the action of IFN. Our preliminary data demonstrate that peripheral dermal infection with VACV, which is normally restricted to the site of infection, causes death of mice lacking STAT1. Importantly, our preliminary data also indicate that ablation or depletion of all three IFNs did not confer lethal susceptibility to dermal VACV, indicating that the lethal phenotype of STAT1-deficient mice is likely a product of IFN-independent STAT1 signaling. A role for STAT1 has been implicated in other signaling pathways, such as those mediated by CD117 (c-kit), IL-27R, IL-21R and a number of Toll-Like Receptors (TLR). Our system, where we have a non-lethal infection in IFN-deficient animals, but a lethal phenotype in STAT1-deficient mice, offers us a unique opportunity to probe the IFN-independent role of STAT1 in protective antiviral immunity. We will examine the IFN-independent role of STAT1 in 2 Specific Aims. In Aim 1, we will compare the host range of VACV, along with the innate and adaptive anti-VACV immune responses, in mice lacking STAT1 or all three IFN receptors. Using this strategy we can identify IFN- independent STAT1-mediated events that may be responsible for protection against lethal VACV challenge. In Aim 2, we will examine STAT1 phosphorylation in mice lacking all three IFN receptors, as well as target genes where expression in induced in a STAT1-dependent, IFN-independent manner. At the conclusion of the proposed investigation we will have identified cells, immune processes and target genes that can provide the basis for a future RO1 proposal investigating IFN-independent STAT1-mediated antiviral immunity.

病毒性皮肤感染是发病率和死亡率的重要原因，有数百万人感染 传染性软疣痘病毒（MCV）。牛痘病毒（Vaccinia Virus，VACV） 在天花根除计划中，它被用来为数亿人接种疫苗， 许多广泛使用的病毒疫苗载体的骨架。免疫系统的目标是限制病毒 直到适应性免疫反应可以安装，将清除病毒。干扰素（IFN）是一种 上调IFN刺激基因（ISG）以限制病毒复制和传播的蛋白质细胞因子家族 并且还通过募集和激活先天性和效应免疫细胞来激活免疫应答 人口。IFN家族由I型、II型和III型组成，每种都使用单独的受体。所有IFN受体 通过Janus激酶（JAK）/信号转导和转录激活因子（STAT）途径。 STAT 1通过与许多其他STAT蛋白相互作用来传递信号，以抑制受体后的信号。 干扰素的结合。在IFN受体信号传导后，STAT 1被磷酸化，随后发生核转位 导致大量ISG的激活。STAT 1的缺失可以显著降低免疫反应 缺乏STAT 1的小鼠经常死于病毒的全身性攻击，包括 VACV。由于IFN信号和STAT 1的紧密联系，STAT 1缺陷小鼠的致死表型 在病毒攻击时，最常被认为是由于缺乏IFN的作用。我们的初步数据 表明VACV的外周皮肤感染，通常限于感染部位， 导致缺乏STAT 1的小鼠死亡。重要的是，我们的初步数据还表明，消融或耗尽 所有三种IFN的致死性表型并不赋予对皮肤VACV的致死性易感性，表明 STAT 1缺陷小鼠可能是IFN-非依赖性STAT 1信号转导的产物。STAT 1的作用是 参与其他信号传导途径，如由CD 117（c-kit）、IL-27 R、IL-21 R和许多 Toll样受体（TLR）我们的系统，在IFN缺乏的动物中，我们有一个非致命的感染，但 STAT 1缺陷小鼠的致死表型，为我们提供了一个独特的机会，以探测IFN-依赖的作用， STAT 1在保护性抗病毒免疫中的作用我们将在2个特定目标中研究STAT 1的IFN独立作用。 在目的1中，我们将比较VACV的宿主范围，沿着先天性和适应性抗VACV免疫 在缺乏STAT 1或所有三种IFN受体的小鼠中，使用这种策略，我们可以识别IFN- 独立的STAT 1介导的事件，可能负责保护免受致命的VACV攻击。在 目的2，我们将在缺乏所有三种IFN受体以及靶基因的小鼠中检测STAT 1的磷酸化 其中表达以STAT 1依赖性、IFN非依赖性方式诱导。结束时 建议的调查，我们将确定细胞，免疫过程和靶基因，可以提供 未来RO 1提案的基础是研究非干扰素依赖性STAT 1介导的抗病毒免疫。