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; 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.

病毒皮肤感染是发病率和死亡率的重要原因，数百万人感染了 全球伴有鼠膜软体动物contagiosum病毒（MCV）。相关的痘病毒疫苗病毒（VACV） 在天花根除计划期间，被用来免疫数亿人，并且仍然是 许多广泛使用的病毒疫苗向量的骨干。免疫系统的目的是限制病毒 扩散直到可以安装自适应免疫反应，以清除病毒。干扰素（IFN）是 上调IFN刺激基因（ISG）以限制病毒复制和扩散的蛋白质细胞因子家族 并通过募集和激活先天和效应器免疫细胞来激活免疫反应 人群。 IFN家族由I型，II和III组成，每个家族都使用单独的受体组成。所有IFN受体 通过Janus激酶（JAK）/信号换能器和转录（STAT）途径激活剂信号。 STAT1通过与许多其他Stat蛋白相互作用来传递受体传递信号的STAT1信号 IFN的结合。 IFN受体信号传导后，STAT1被磷酸化并随后进行核转运 导致大量ISG的激活。 STAT1的删除可以大大减少免疫反应 在体外和体内IFN，缺乏STAT1的小鼠通常会屈服于病毒的全身挑战，包括 vacv。由于IFN信号和STAT1的紧密连接，STAT1缺陷小鼠的致命表型 在病毒挑战时，通常被认为是由于缺乏IFN的作用。我们的初步数据 证明通常限于感染部位的VAVV外周皮肤感染， 导致缺乏STAT1的小鼠死亡。重要的是，我们的初步数据还表明消融或耗尽 在这三个IFN中，没有赋予对皮肤Vacv的致命敏感性，表明 STAT1缺陷小鼠可能是IFN独立的STAT1信号传导的产物。 STAT1的角色已经 与其他信号通路有关，例如由CD117（C-KIT）介导的途径，IL-27R，IL-21R和一个数字 Toll样受体（TLR）。我们的系统，我们在IFN缺乏动物中患有非致命感染，但 STAT1缺陷小鼠的致命表型为我们提供了一个独特的机会，可以探究IFN独立的作用 保护性抗病毒免疫中的STAT1。我们将研究STAT1在2个特定目标中与IFN无关的作用。 在AIM 1中，我们将比较VAVV的宿主范围，以及先天和自适应抗VACV免疫 在缺乏STAT1或所有三个IFN受体的小鼠中的反应。使用此策略，我们可以确定 独立的STAT1介导的事件，可能导致保护致命VAVV挑战。在 AIM 2，我们将检查缺乏所有三个IFN受体的小鼠中的STAT1磷酸化以及靶基因 以STAT1依赖性，IFN独立的方式诱导的表达。在结束时 拟议的研究我们将确定可以提供的细胞，免疫过程和靶基因 未来的RO1提案的基础研究了与IFN无关的STAT1介导的抗病毒免疫。