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.

总结 该建议的重点是表征果蝇的先天抗病毒免疫反应。 特别地，对DNA病毒（无脊椎动物虹彩病毒6）感染的应答将是 表征了在初步研究中，发现IIV-6感染诱导了 一组JAK-STAT应答基因，称为Turandots或Tot基因。8 Tot 基因编码一个家族的快速进化，小，分泌蛋白质，没有已知的功能。 病毒诱导的Tot表达需要病毒复制、p38 b MAPK信号传导和JAK-STAT activation.此外，未配对（UPD）细胞因子，这是唯一已知的JAK-STAT 与哺乳动物IL-6有远亲关系的配体在DNA病毒感染后上调， p38 b依赖性在体内，p38 b和JAK-STAT途径都是必需的， 从DNA病毒感染中存活。总之，这些数据表明，病毒感染导致p38 b 激活和随后分泌的未配对细胞因子的产生。反过来， 激活JAK-STAT信号传导以诱导Tot基因和其它靶基因的表达。 此外，我们发现DNA病毒感染的细胞产生可溶性因子， 保护幼稚细胞免受病毒感染。这种抗病毒活性干扰了两种DNA的感染， RNA病毒。因此，DNA病毒感染在果蝇细胞中诱导广泛的抗病毒状态。 考虑到Tots的诱导表达和抗微生物肽样特征， 这些发现使我们假设病毒诱导的图兰朵蛋白的功能是分泌的， 抗病毒药目的1探索了Tots作为抗病毒肽的潜力，而目的2提出了一种新的抗病毒肽。 无偏方法表征和鉴定DNA诱导的可溶性抗病毒活性 病毒感染。本研究旨在探讨Tot基因诱导的分子机制 并表征DNA病毒诱导的抗病毒状态。