The role of UBXNs in antiviral immunity

UBXNs 在抗病毒免疫中的作用

基本信息

批准号：
10356179
负责人：
PENGHUA WANG
金额：
$ 41.09万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
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/10356179
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 Cre lox recombination system 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 Persons 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 response transmission process ubiquitin-protein ligase vaccine development viral DNA

项目摘要

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，根据 World 数据，全球患病率约为 67% 卫生组织。免疫功能低下的人，例如晚期艾滋病毒感染者感染 HSV-1 会导致更严重的症状，例如脑炎或角膜炎，但很少见。母婴传播可能发生，尽管很少见，估计每 10,000 名新生儿中就有 1 人发生母婴传播在全球范围内，但可能导致持久的神经功能障碍或死亡。蚊媒基孔肯雅热披膜病毒科病毒 (CHIKV) 重新成为重大公共卫生威胁全世界。 CHIKV 引起急性和慢性致残性关节痛以及长期神经系统疾病失调。累计病例超180万例，直接或间接死亡436人与 CHIKV 相关，自 2013 年底入侵加勒比海以来在美洲出现。该项目研究了一个我们知之甚少的基因家族 UBXNs 的生理作用，通过遗传、分子控制小鼠 HSV-1 和 CHIKV 感染及疾病发病机制生物学、生化和免疫学方法，并可能最终有助于疫苗和治疗方法的开发。我们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。我们随后将了解 UBXN 如何调节先天免疫系统，特别是刺激免疫系统干扰素基因（STING）途径，限制病毒感染。 STING 感知环 GMP-AMP (cGAMP)，由 cGAMP 合酶 (cGAS) 快速合成的第二信使对病毒 DNA 做出反应，然后诱导 I 型干扰素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证明： STING 对于小鼠模型中 RNA 病毒感染的控制也很重要。底层的然而，分子机制仍不清楚。在这个项目结束时，我们希望解决我们对 STING 在先天免疫中的作用的知识和理解上的差距 RNA 病毒和 UBXN3B 调节 STING 介导的先天抗病毒免疫反应，并增加我们对宿主对人类医学病毒的免疫反应的了解意义。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Endogenous Retrovirus-Derived Long Noncoding RNA Enhances Innate Immune Responses via Derepressing RELA Expression.

内源性逆转录病毒衍生的长非编码 RNA 通过去抑制 RELA 表达来增强先天免疫反应。

DOI：
发表时间：
2019
期刊：
影响因子：
6.4
作者：
Zhou, Bin;Qi, Fei;Wu, Fangyi;Nie, Hongbo;Song, Yifan;Shao, Lu;Han, Jingxuan;Wu, Zhen;Saiyin, Hexige;Wei, Gang;Wang, Penghua;Ni, Ting;Qian, Feng
通讯作者：
Qian, Feng

Lack of efficacy of ivermectin for prevention of a lethal Zika virus infection in a murine system.

伊维菌素缺乏预防小鼠系统中致命的寨卡病毒感染的功效。