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.

项目概要 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、急性弛缓性脊髓炎。疾病 结果可能是严重或致命的，特别是对于新生儿和儿童。宿主先天免疫反应 通常控制这些病毒。然而，介导该宿主的细胞内在抗病毒机制 防御没有明确定义。在这里，我们建议鉴定和表征编码宿主抗病毒基因 组成型表达（非诱导型）和干扰素刺激基因（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，我们最近证明它会抑制 肠道病毒通过靶向病毒蛋白进行降解来复制。我们假设 TRIM7 是一个泛 体外和体内肠道病毒限制因子。在目标 2 中，我们将利用我们在 ISG 筛选方面的专业知识 技术来检验只有一组有限的基因是干扰素诱导的真正效应器的假设 对肠道病毒 A-D 的抗病毒反应。我们将描述抗病毒效应作用机制的特征，并且我们 将使用新型脂质纳米颗粒基因传递策略来证明体内抗病毒功效。两个目标 将通过基于细胞的检测中的生化、病毒学和遗传学方法的结合来实现 以及肠道病毒感染和发病机制的小鼠模型。完成拟议目标将 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。这些研究还可能为泛肠道病毒疗法的发展提供信息 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。

• 发表时间: 2022-10-12
• 作者: Fan, Wenchun;McDougal, Matthew B;Schoggins, John W
• 通讯作者: Schoggins, John W