DNA sensors and associated signaling pathways in the innate immune response

先天免疫反应中的 DNA 传感器和相关信号通路

• 批准号: 8297717
• 负责人: Katherine A. Fitzgerald
• 金额: $ 36.52万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8297717
• 关键词: AIM2 gene; Adjuvant; Affect; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Automobile Driving; Boxing; Caspase-1; Cell Line; Cells; Complex; DNA; DNA Vaccines; DNA Viruses; DNA-Binding Proteins; Disease; Family member; Gene Expression Regulation; Genes; Genetic Transcription; Herpesviridae; Host Defense; Immune; Immune response; Immune system; Immunity; In Vitro; Infection; Inflammatory; Inflammatory Response; Interferon Activation; Interferon Type I; Interferons; Interleukin-1; Interleukin-18; Invaded; Kaposi Sarcoma; Knockout Mice; Laboratories; Lead; Ligands; Mediating; Molecular; Mus; Natural Immunity; Nuclear; Nucleic Acids; Orthologous Gene; Pathogenesis; Pathology; Pathway interactions; Play; Process; Production; Proteins; RNA; Role; Signal Pathway; Signal Transduction; Systemic Lupus Erythematosus; TANK-binding kinase 1; TBK1 gene; Testing; Therapeutic; Time; Viral; Virus; Virus Diseases; Work; antimicrobial; base; cytokine; design; fighting; gene induction; helicase; human IRF3 protein; in vivo; interferon regulatory factor-3; marenostrin; microbial; microbial host; new therapeutic target; novel therapeutics; pathogen; prevent; receptor; response; sensor; small hairpin RNA; vaccine efficacy; viral DNA

DESCRIPTION (provided by applicant): RNA and DNA elicit inflammatory responses which are critical for anti-microbial immunity. DNA is a potent trigger of inflammatory cytokine and type I IFN gene transcription, as well as caspase-1-mediated processing of the pro-inflammatory cytokines IL-1? and IL-18. Growing evidence indicates that DNA recognition is central not only to anti-microbial host defenses but is also a major contributor to the adjuvant activity of DNA vaccines as well as the pathology associated with autoimmune diseases such as Systemic Lupus Erythematosis. It is therefore critical that we understand the molecular basis of DNA recognition. Recent work from our group has implicated the PYHIN family members Absent in melanoma-2 (AIM2) and the interferon-inducible protein (IFI16) as sensors of microbial DNA. Both proteins bind DNA via HIN domains. AIM2 engages ASC via a pyrin domain to form a caspase-1 activating inflammasome while IFI16 activates a cytosolic signaling pathway involving Stimulator of IFN genes (STING), TANK binding kinase-1 (TBK-1) and interferon regulatory factor 3 (IRF3) to regulate transcription of type I IFN genes. Knockdown of IFI16, or its murine ortholog p204 prevents viral DNA from triggering IRF3 activation and IFN? gene induction, while not affecting responses to cytosolic RNA. Recent evidence also indicates that IFI16 can form an inflammasome in responses to nuclear sensing of Kaposi's Sarcoma Herpes Virus infection. Additional work from our laboratories has also implicated the DEAD box helicase DEAD box protein 3x (DDX3x) in the TBK1/IRF3 signaling pathway important for both RNA and cytoplasmic DNA pathways (including for IFI16), but its role in innate immunity remains to be fully characterized. The underlying hypothesis to be tested in this proposal is that IFI16 plays a central role in innate immunity and host-defense to microbial pathogens by regulating inflammatory responses and that DDX3x is an important downstream component of the IFI16 signaling pathway. We propose to explore the molecular mechanisms of IFI16 activation and define the role of IFI16 and DDX3x in anti-viral host-defenses. This project will increase our understanding of how the innate immune system senses pathogens, leading to novel therapeutic targets. PUBLIC HEALTH RELEVANCE: Cells have immune sensors that detect DNA from invading viruses, giving rise to appropriate protective anti-viral cellular responses controlled by interferons. These responses are at times inappropriately activated by self-DNA, leading to pathological autoimmune responses. We have discovered that a cellular protein called IFI16 is such a sensor, and understanding how it works will lead to therapies to enhance or dampen immune responses to fight pathogens or suppressing autoimmune responses respectively.

描述（由申请人提供）：RNA 和 DNA 引发炎症反应，这对于抗微生物免疫至关重要。 DNA 是炎症细胞因子和类型的有效触发因素 I IFN 基因转录，以及 caspase-1 介导的促炎细胞因子 IL-1？和IL-18。越来越多的证据表明，DNA 识别不仅对于抗微生物宿主防御至关重要，而且也是 DNA 疫苗佐剂活性以及与系统性红斑狼疮等自身免疫性疾病相关病理学的主要贡献者。因此，了解 DNA 识别的分子基础至关重要。 我们小组最近的工作表明，黑色素瘤 2 中不存在的 PYHIN 家族成员 (AIM2) 和干扰素诱导蛋白 (IFI16) 作为微生物 DNA 的传感器。两种蛋白质均通过 HIN 结构域结合 DNA。 AIM2 通过 Pyrin 结构域与 ASC 结合，形成 caspase-1 激活炎症小体，而 IFI16 则激活涉及 IFN 基因刺激物 (STING)、TANK 结合激酶 1 (TBK-1) 和干扰素调节因子 3 (IRF3) 的胞质信号传导通路，从而调节 I 型 IFN 基因的转录。敲低 IFI16 或其小鼠直系同源物 p204 可防止病毒 DNA 触发 IRF3 激活和 IFN？基因诱导，同时不影响对胞质 RNA 的反应。最近的证据还表明，IFI16 可以形成炎症小体，以响应卡波西肉瘤疱疹病毒感染的核感应。我们实验室的其他工作还表明，TBK1/IRF3 信号通路中的 DEAD 盒解旋酶 DEAD 盒蛋白 3x (DDX3x) 对 RNA 和细胞质 DNA 通路（包括 IFI16）都很重要，但其在先天免疫中的作用仍有待充分研究。特点。 本提案要测试的基本假设是 IFI16 发挥着 DDX3x 通过调节炎症反应在先天免疫和宿主对微生物病原体的防御中发挥核心作用，并且 DDX3x 是 IFI16 信号通路的重要下游组件。我们建议探索 IFI16 激活的分子机制，并定义 IFI16 和 DDX3x 在抗病毒宿主防御中的作用。该项目将增进我们对先天免疫系统如何感知病原体的理解，从而找到新的治疗靶点。 公共健康相关性：细胞具有免疫传感器，可以检测入侵病毒的 DNA，从而产生由干扰素控制的适当的保护性抗病毒细胞反应。这些反应有时会被自身 DNA 不当激活，导致病理性自身免疫反应。我们发现一种名为 IFI16 的细胞蛋白就是这样一种传感器，了解它的工作原理将有助于开发出增强或抑制免疫反应以对抗病原体或抑制自身免疫反应的疗法。