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: 10449724
• 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 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10449724
• 关键词: Address; Affect; Alphavirus; Amino Acids; Antiviral Agents; Antiviral Response; Attenuated; Binding; Biochemical; Biochemical Genetics; 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; Intuition; 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; Proteins; Publishing; RNA Viruses; Resistance; Role; Technology; Testing; Therapeutic; Tissues; Ubiquitination; Viral; Viral Proteins; Virus; Virus Diseases; Virus Replication; Work; acute flaccid myelitis; anti-viral efficacy; base; 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 肠道病毒A、B、C、D是重要的病原体，可引起一系列疾病，包括心肌炎、 脑炎、脑膜炎、结膜炎、手足口病和急性弛缓性脊髓炎。疾病 后果可能是严重的或致命的，特别是在新生儿和儿童中。宿主的先天免疫反应 通常可以控制这些病毒。然而，介导这种宿主的细胞内在的抗病毒机制 防守没有很好地定义。在这里，我们建议识别和表征宿主抗病毒基因编码 结构性表达(非诱导)和干扰素刺激基因(ISG)抗病毒效应物。在……里面 Aim1，我们将检测TRIM7，一种结构性表达的E3连接酶，我们最近发现它具有抑制作用 通过以病毒蛋白为目标进行降解的肠道病毒复制。我们假设TRIM7是一个平底锅- 肠道病毒限制因子的体内外研究。在目标2中，我们将利用我们在ISG筛查方面的专业知识 测试只有一组有限的基因才是干扰素诱导的真正效应者的假设的技术 肠道病毒A-D的抗病毒反应我们将描述抗病毒效应器的作用机制，我们 将使用新的脂质纳米颗粒基因传递策略来展示体内的抗病毒效果。这两个目标 将通过在基于细胞的分析中结合生化、病毒学和遗传学方法来实现 并在小鼠模型上进行肠道病毒感染及发病机制的研究。完成拟议的目标将 提供有关赋予细胞内在保护作用的特定分子的基础知识 这些肠道病毒。这些研究可能为泛肠道病毒疗法的发展提供额外的信息。 基于这些天然产生的抗病毒防御蛋白的机制。