DNA Virus Infection Induces an Anti-Viral State in Drosophila

DNA病毒感染在果蝇中诱导抗病毒状态

• 批准号: 9412809
• 负责人: Neal Silverman
• 金额: $ 20.94万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-16 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9412809
• 关键词: Antiviral Agents; Arthropods; Biochemical; Cells; Characteristics; Chikungunya virus; Complement Factor B; DNA Virus Infections; DNA Viruses; Data; Distant; Drosophila genus; Face; Family; Gene Expression; Gene Targeting; Genes; Homologous Gene; Human; Immune response; Individual; Infection; Insect Vectors; Insecta; Interferons; Interleukin-6; Invertebrates; Kinetics; Lead; Ligands; MAP Kinase Gene; Mammalian Cell; Maps; Molecular; Molecular Probes; Mosquito Control; Natural Immunity; Pathway interactions; Peptides; Production; Property; Proteins; RNA Interference; RNA Viruses; Role; Signal Transduction; Source; System; Viral; Viral Vector; Virus; Virus Diseases; Virus Replication; Zika Virus; antimicrobial peptide; antiviral immunity; combat; cytokine; gene induction; in vivo; inducible gene expression; novel; peptide A; protein function; response; vector

Summary This proposal is focused on characterizing the innate antiviral immune response of Drosophila. In particular, the response to infection with a DNA virus, Invertebrate Iridescent Virus 6, will be characterized. In preliminary studies,IIV-6 infection was found to induce the robust expression of a group of JAK-STAT responsive genes known as the Turandots, or Tot, genes. The eight Tot genes encode of a family of rapidly-evolving, small, secreted proteins with no known functions. Viral-induced Tot expression requires viral replication, p38b MAPK signaling, and JAK-STAT activation. Additionally, the Unpaired (UPD) cytokines, which are the only known JAK-STAT ligands, distantly related to mammalian IL-6, are up-regulated after DNA virus infection in a p38b-dependent manner. In vivo, both the p38b and JAK-STAT pathways are required for survival from DNA virus infection. Together, this data suggests that viral infection leads to p38b activation and the subsequent production of the secreted Unpaired cytokines. UPDs, in turn, activate JAK-STAT signaling to induce Tot gene expression and other target genes. In addition, we have found that DNA virus-infected cells produce soluble factors that protect naive cells from viral infection. This antiviral activity interferes with infection of both DNA and RNA viruses. Thus, DNA virus infection induces a broad antiviral state in Drosophila cells. Given the the inducible expression and antimicrobial peptide-like characteristics of the Tots, these findings lead us to hypothesize that virus-induced Turandot proteins function as secreted antivirals. Aim 1 explores the potential of the Tots as antiviral peptides, while Aim 2 proposes an unbiased approach to characterize and identify the soluble antiviral activity induced by DNA virus infection. Altogether, this project will probe the molecular mechanism of Tot gene induction and characterize the DNA virus-induced antiviral state.

摘要 这项建议的重点是描述果蝇的先天抗病毒免疫反应。 特别是，对感染DNA病毒--无脊椎动物虹彩病毒6的反应将是 特色化的。在初步研究中，IIV-6感染被发现诱导了 一组JAK-STAT反应基因，称为图兰点基因，或Tot基因。《八大通》 基因编码了一个快速进化的、小的、分泌的蛋白质家族，这些蛋白质没有已知的功能。 病毒诱导的Tot表达需要病毒复制、p38b MAPK信号转导和JAK状态 激活。此外，未配对(UPD)细胞因子是唯一已知的JAK状态 与哺乳动物IL-6有远亲关系的配体在DNA病毒感染后表达上调 P38b依赖方式。在活体中，p38b和JAK-STAT通路都是必需的 从DNA病毒感染中存活下来。综上所述，这些数据表明病毒感染导致p38b 激活和随后分泌的未配对细胞因子的产生。反过来，UPDS， 激活JAK-STAT信号，诱导Tot基因和其他靶基因表达。 此外，我们还发现，DNA病毒感染的细胞产生的可溶性因子 保护幼稚细胞免受病毒感染。这种抗病毒活性干扰了这两种DNA的感染 和RNA病毒。因此，DNA病毒感染在果蝇细胞中诱导了广泛的抗病毒状态。 鉴于Tots的诱导性表达和抗菌肽样特性， 这些fi编码使我们假设病毒诱导的图兰朵蛋白的功能是分泌的 抗病毒药物。目标1探索了Tots作为抗病毒多肽的潜力，而目标2提出了一种 无偏方法鉴定DNA诱导的可溶性抗病毒活性 病毒感染。综上所述，本项目将探索Tot基因诱导的分子机制 并表征DNA病毒诱导的抗病毒状态。