The role of UBXNs in antiviral immunity

UBXNs 在抗病毒免疫中的作用

• 批准号: 10084799
• 负责人: PENGHUA WANG
• 金额: $ 33.47万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10084799
• 关键词: Acute; Address; Adult; Americas; Animals; Antiviral Agents; Arthralgia; Binding; Biochemical; Biological; Biological Assay; Birth; Caribbean region; Cell Cycle; Cell physiology; Cells; Cessation of life; Chikungunya virus; Chronic; Complex; Cyclic GMP; DNA Viruses; Data; Development; Disease; Embryonic Development; Encephalitis; Family; Fluorescence; Gene Activation; Genes; Genetic; HIV Infections; Herpesvirus 1; Human; Immune Response Genes; Immune response; Immune signaling; Immunocompromised Host; Immunologics; Immunoprecipitation; Impairment; In Vitro; Infant; Infection; Innate Immune System; Interferon Type I; Keratitis; Knock-out; Knowledge; Lead; Mediating; Medical; Molecular; Mothers; Mus; Natural Immunity; Neurologic; Pathogenesis; Pathogenicity; Pathway interactions; Physiological; Predisposition; Prevalence; Proteins; Public Health; Publishing; RNA Virus Infections; RNA Viruses; Receptor Signaling; Regulation; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Stimulator of Interferon Genes; Symptoms; TRIM Motif; Tamoxifen; Therapeutic; Time; Togaviridae; Toll-like receptors; Ubiquitination; Vaccines; Vesicle; Vesicular stomatitis Indiana virus; Viral Pathogenesis; Virus; Virus Diseases; Virus Replication; West Nile virus; Work; World Health Organization; adaptive immune response; antiviral immunity; chikungunya infection; cofactor; disability; early embryonic stage; human pathogen; in vivo; insight; mosquito-borne; mouse model; nervous system disorder; p97 ATPase; protein degradation; recombinase-mediated cassette exchange; response; transmission process; ubiquitin-protein ligase; vaccine development; viral DNA

HSV-1 is an important human pathogen, with a global prevalence of ~67% according to World Health Organization. In immunocompromised people, such as those with advanced HIV infection, HSV-1 cause more severe symptoms such as encephalitis or keratitis though rarely. Mother-to-infant transmission can occur, though rarely, estimated 1 out of every 10,000 births globally, but can lead to lasting neurologic disability or death. The mosquito-borne Chikungunya virus (CHIKV) of the Togaviridae family is re-emerging as a significant public health threat world-wide. CHIKV causes acute and chronic crippling arthralgia and long-term neurological disorders. The cumulative cases are over 1.8 million, with 436 deaths directly or indirectly related to CHIKV, in Americas since its invasion into the Caribbean in late 2013. This project investigates the physiological roles of a family of poorly understood genes, UBXNs, in controlling HSV-1 and CHIKV infection and disease pathogenesis in mice via genetic, molecular biological, biochemical and immunological approaches, and may ultimately contribute to development of vaccines and therapeutics. We will first examine the changes in disease pathogenesis and antiviral immune responses of gene deficient animals and cells. We will then understand how UBXNs regulate the innate immune system, specifically the stimulator of interferon genes (STING) pathway, to limit viral infection. STING senses cyclic GMP-AMP (cGAMP), a second messenger that is rapidly synthesized by cGAMP synthase (cGAS) in response to viral DNA, and then induces expression of type I IFNs and other antiviral molecules. Our study with West Nile virus (WNV) and other recent studies consistently demonstrate that STING is also important for the control of RNA virus infection in mouse models. The underlying molecular mechanism, however, remain largely unclear. At the end of this project, we hope to address a gap in our knowledge and understanding of the role of STING in innate immunity to RNA viruses and UBXN3B in regulation of STING-mediated innate antiviral immune response, and increase our knowledge in the host immune responses to human viruses of medical significance.

HSV-1是一种重要的人类病原体，据世界卫生组织统计，全球HSV-1感染率约为67% 卫生组织。免疫功能低下的人，如晚期艾滋病毒携带者 感染，HSV-1会引起更严重的症状，如脑炎或角膜炎，尽管很少见。 母婴传播可能会发生，尽管很少见，但估计每10,000名新生儿中就有1名 在全球范围内，但可能导致持久的神经残疾或死亡。蚊媒基孔肯雅热 Togaviridae家族的CHIKV病毒正在重新成为一个重大的公共卫生威胁 世界范围内。CHIKV导致急性和慢性致残性关节痛和长期神经疾病 精神错乱。累计病例超过180万例，直接或间接死亡436例 自2013年底入侵加勒比海以来，美洲出现了与CHIKV有关的病毒。这个项目 研究了一个鲜为人知的基因家族UBXN的生理作用。 从遗传学、分子水平控制HSV-1和CHIKV感染及其致病机制 生物、生化和免疫学方法，并最终可能有助于 疫苗和疗法的发展。我们将首先检查疾病的变化 基因缺陷动物和细胞的发病机制和抗病毒免疫反应。到时候我们会的 了解UBXN如何调节先天免疫系统，特别是刺激 干扰素基因(STING)途径，以限制病毒感染。刺痛感觉循环GMP-AMP (CGAMP)是由cGAMP合成酶(CGAS)快速合成的第二信使。 对病毒DNA的反应，然后诱导I型IFN和其他抗病毒分子的表达。 我们对西尼罗河病毒(WNV)的研究和其他最近的研究一致表明 刺痛对于控制小鼠模型中的RNA病毒感染也很重要。潜在的 然而，分子机制在很大程度上仍不清楚。在这个项目结束时，我们希望 解决我们对刺痛在先天免疫中的作用的认识和理解上的差距 RNA病毒和UBXN3B在调节刺激性先天抗病毒免疫反应中的作用 并增加我们对宿主免疫应答人类病毒的医学知识 意义。