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

基本信息

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
项目类别：
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

项目摘要

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和死亡的一个重要原因，有数百万人被感染传染性软疣病毒（MCV）在全球范围内传播。相关的痘病毒痘苗病毒（VACV）在消灭天花计划期间用于为数亿人提供免疫接种，并且仍然是一种许多广泛使用的病毒疫苗载体的骨干。免疫系统的目标是限制病毒传播，直到可以发起适应性免疫反应来清除病毒。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还通过招募和激活先天免疫细胞和效应免疫细胞来激活免疫反应人口。 IFN 家族由 I 型、II 型和 III 型组成，每种都使用不同的受体。所有干扰素受体通过 Janus 激酶 (JAK)/信号转导和转录激活剂 (STAT) 途径发出信号。 STAT1 信号通过与许多其他 STAT 蛋白相互作用来在受体之后转导信号 IFN 的结合。 IFN 受体信号传导后，STAT1 被磷酸化并随后发生核转位导致大量ISG的激活。 STAT1的缺失可以显着降低免疫反应体内和体外均受到 IFN 的影响，缺乏 STAT1 的小鼠经常会死于病毒的全身攻击，包括疫苗接种。由于 IFN 信号传导与 STAT1 紧密相连，STAT1 缺陷小鼠的致死表型病毒攻击后，通常认为是由于缺乏 IFN 的作用。我们的初步数据证明外周真皮感染 VACV，通常仅限于感染部位，导致缺乏 STAT1 的小鼠死亡。重要的是，我们的初步数据还表明，消融或耗尽所有三种干扰素均不赋予对真皮 VACV 的致死敏感性，表明致死表型 STAT1 缺陷小鼠可能是不依赖 IFN 的 STAT1 信号传导的产物。 STAT1 的作用是参与其他信号传导途径，例如由 CD117 (c-kit)、IL-27R、IL-21R 和许多介导的信号传导途径 Toll 样受体 (TLR)。在我们的系统中，我们对缺乏干扰素的动物进行了非致命性感染，但是 STAT1 缺陷小鼠的致死表型为我们提供了一个独特的机会来探索 IFN 独立的作用 STAT1在保护性抗病毒免疫中的作用。我们将在 2 个具体目标中研究 STAT1 的独立于 IFN 的作用。在目标 1 中，我们将比较 VACV 的宿主范围，以及先天性和适应性抗 VACV 免疫缺乏 STAT1 或所有三种 IFN 受体的小鼠的反应。使用这种策略，我们可以识别 IFN- 独立的 STAT1 介导的事件可能负责防止致命的 VACV 挑战。在目标 2，我们将检查缺乏所有三种 IFN 受体以及靶基因的小鼠中的 STAT1 磷酸化其中表达以 STAT1 依赖性、非 IFN 依赖性方式诱导。会议结束时拟议的研究，我们将确定可以提供未来 RO1 提案研究 IFN 独立的 STAT1 介导的抗病毒免疫的基础。