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引起炎症反应，这对抗微生物免疫至关重要。DNA是炎症细胞因子和类型的有力触发器