Cell intrinsic antiviral mechanisms targeting human enteroviruses

针对人类肠道病毒的细胞内在抗病毒机制

• 批准号: 10595616
• 负责人: John W. Schoggins
• 金额: $ 46.86万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-22 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595616
• 关键词: Address; Affect; Alphavirus; Amino Acids; Antiviral Agents; Antiviral Response; Attenuated; Binding; Biochemical; Biological; Biological Assay; Biology; Cell Culture Techniques; Cells; Child; Clustered Regularly Interspaced Short Palindromic Repeats; Conjunctivitis; Defense Mechanisms; Development; Disease; Disease Outbreaks; Disease Outcome; Echo Viruses; Ectopic Expression; Encephalitis; Enterovirus; Enterovirus Infections; Family Picornaviridae; Flavivirus; Gene Delivery; Gene Targeting; Genes; Genetic study; Goals; Hand, Foot and Mouth Disease; Host Defense; Host Defense Mechanism; Human; Impairment; In Vitro; Innate Immune Response; Innate Immune System; Interferons; Knock-out; Knockout Mice; Knowledge; Libraries; Mediating; Meningitis; Messenger RNA; Microbe; Microbiology; Modeling; Molecular; Mus; Myocarditis; Natural Immunity; Nature; Normal Cell; Outcome; Pancreatitis; Pathogenesis; Pathogenicity; Predisposition; Proteins; Publishing; RNA Viruses; Resistance; Role; Technology; Testing; Therapeutic; Tissues; Ubiquitination; Viral; Viral Genes; Viral Physiology; Viral Proteins; Virus; Virus Diseases; Virus Replication; Work; acute flaccid myelitis; anti-viral efficacy; boys; cDNA Library; cost; early screening; fitness; gain of function; genetic approach; genome-wide; healing; human pathogen; in vivo; lipid nanoparticle; loss of function; mouse model; neonate; novel; pathogen; pathogenic virus; pressure; protein degradation; screening; therapy development; trend; ubiquitin-protein ligase

Project Summary Enteroviruses A, B, C, D are important pathogens that can cause a range of diseases including myocarditis, encephalitis, meningitis, conjunctivitis, hand, foot and mouth disease, and acute flaccid myelitis. Disease outcomes can be severe or fatal, particularly in neonates and children. The host innate immune response generally controls these viruses. However, the cell intrinsic antiviral mechanisms that mediate this host defense are not well defined. Here, we propose to identify and characterize host antiviral genes encoding both constitutively expressed (non-inducible) and interferon-stimulated gene (ISG) antiviral effectors. In Aim1, we will examine TRIM7, a constitutively expressed E3 ligase that we recently showed inhibits enterovirus replication by targeting a viral protein for degradation. We hypothesize that TRIM7 is a pan- enterovirus restriction factor in vitro and in vivo. In Aim 2, we will leverage our expertise in ISG screening technology to test the hypothesis that only a limited set of genes are true effectors of the interferon-induced antiviral response to enteroviruses A-D. We will characterize antiviral effector mechanisms of action, and we will use novel lipid nanoparticle gene delivery strategies to demonstrate antiviral efficacy in vivo. Both Aims will be achieved by a combination of biochemical, virological, and genetic approaches in cell-based assays and in mouse models of enterovirus infection and pathogenesis. Completion of the proposed aims will provide fundamental knowledge about the specific molecules that confer cell intrinsic protection against these enteroviruses. These studies may additionally inform the development of pan-enterovirus therapies based on the mechanisms of these naturally occurring antiviral defense proteins.

项目摘要 肠病毒A，B，C，D是重要的病原体，可引起多种疾病，包括心肌炎， 脑炎，脑膜炎，结膜炎，手，脚和口腔疾病以及急性松弛的脊髓炎。疾病 结果可能是严重的或致命的，尤其是在新生儿和儿童中。宿主先天免疫反应 通常控制这些病毒。但是，介导该宿主的细胞固有抗病毒机制 防御不是很好的定义。在这里，我们建议识别和表征编码的宿主抗病毒基因 组成型表达（不可诱导）和干扰素刺激的基因（ISG）抗病毒效应子。在 AIM1，我们将检查TRIM7，这是一种组成型表达的E3连接酶，我们最近显示出抑制作用 通过靶向病毒蛋白来降解肠病毒复制。我们假设Trim7是一个泛 体外和体内肠病毒限制因子。在AIM 2中，我们将利用我们在ISG筛查中的专业知识 测试仅一组有限基因的假设是干扰素诱导的真正效应子 对肠病毒A-D的抗病毒反应。我们将表征抗病毒效应子的作用机理，我们 将使用新型的脂质纳米颗粒基因递送策略来证明体内抗病毒疗效。两个目标 将通过基于细胞的测定中的生化，病毒学和遗传方法的结合来实现 在肠病毒感染和发病机理的小鼠模型中。拟议的目标的完成将 提供有关赋予细胞固有保护侵害细胞固有保护的特定分子的基本知识 这些肠病毒。这些研究可能还可以告知泛 - 肠病毒疗法的发展 基于这些天然存在的抗病毒防御蛋白的机制。

项目成果

Enterovirus 3C Protease Cleaves TRIM7 To Dampen Its Antiviral Activity.

肠道病毒 3C 蛋白酶会裂解 TRIM7 以减弱其抗病毒活性。

• DOI: 10.1128/jvi.01332-22
• 发表时间: 2022
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Fan,Wenchun;McDougal,MatthewB;Schoggins,JohnW
• 通讯作者: Schoggins,JohnW