Antiviral immunity directed by virus-derived small silencing RNAs in mice

小鼠中病毒源性小RNA沉默指导的抗病毒免疫

• 批准号: 9014138
• 负责人: Shou-Wei Ding
• 金额: $ 37.22万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-15 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9014138
• 关键词: Adult; Antiviral Agents; Area; Arthropods; Biogenesis; Bioterrorism; Categories; Cell Death; Culicidae; DNA Viruses; DNA biosynthesis; Defense Mechanisms; Dengue; Dengue Virus; Detection; Development; Double-Stranded RNA; Epidemic; Exhibits; Genetic; Genome; Goals; HIV; Health; Hepatitis C; Hepatitis C virus; Human; Immune; Immune system; Immunity; Infection; Interferons; Invertebrates; Lead; Length; Liver diseases; Mammalian Cell; Mammals; Mediating; Modeling; Mus; Natural Immunity; Nucleotides; Organism; Paper; Pathogenesis; Plants; Play; Principal Investigator; Process; Production; Property; Proteins; Public Health; Publishing; RNA; RNA Interference; RNA Interference Pathway; RNA Virus Infections; RNA Viruses; RNA replication; RNA-Directed RNA Polymerase; Research; Resistance; Role; Science; Signal Transduction; Small Interfering RNA; System; Therapeutic Intervention; Vaccines; Viral; Viral Physiology; Virus; Virus Diseases; in vivo; influenzavirus; invertebrate host; mouse model; mutant; pandemic disease; pathogen; response; sensor; viral RNA

DESCRIPTION (provided by applicant): Viruses with an RNA genome are important human pathogens and exhibit distinct genetic and immunological properties from DNA viruses. Plant and invertebrate hosts produce virus-derived small interfering RNAs (siRNAs) of 21-24 nucleotides in length to guide specific clearance of RNA viruses by RNA interference (RNAi). However, it has been unclear if the conserved RNAi pathway has a similar antiviral role in mammals. New findings described here and in two recent papers in Science by the principal investigator provide evidence for the induction of antiviral RNAi and specific sterilizing immunity in mice by a mosquito-transmissible positive-strand RNA virus. Preliminary studies also indicate a role for the viral suppression of RNAi in mouse infection and for a known innate immune sensor of RNA viruses in the biogenesis of the predominantly 22- nucleotide viral siRNAs. Using the established mouse model, a complementary set of studies is proposed to characterize the function and mechanism of the mammalian RNAi- mediated antiviral immunity. Moreover, possible regulatory roles of interferon signaling and the interferon-stimulated innate immune sensors of RNA viruses in the new form of mammalian antiviral immunity will be examined. These studies will likely open up a new area of research on the antiviral immunity mechanisms in mammals.

描述（由申请方提供）：具有RNA基因组的病毒是重要的人类病原体，表现出与DNA病毒不同的遗传和免疫学特性。植物和无脊椎动物宿主产生长度为21-24个核苷酸的病毒衍生的小干扰RNA（siRNA），以通过RNA干扰（RNAi）指导RNA病毒的特异性清除。然而，目前尚不清楚保守的RNAi途径是否在哺乳动物中具有类似的抗病毒作用。在这里描述的新发现和最近两篇由主要研究者发表在《科学》杂志上的论文为诱导抗病毒RNAi和特异性杀菌免疫提供了证据 蚊子传播的正链RNA病毒。初步研究还表明RNAi在小鼠感染中的病毒抑制作用以及RNA病毒的已知先天免疫传感器在主要22个核苷酸的病毒siRNA的生物发生中的作用。利用建立的小鼠模型，提出了一组互补的研究来表征哺乳动物RNAi介导的抗病毒免疫的功能和机制。此外，干扰素信号和干扰素刺激的RNA病毒的先天免疫传感器在哺乳动物抗病毒免疫的新形式的可能的调节作用将被检查。这些研究将可能为哺乳动物抗病毒免疫机制的研究开辟新的领域。