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.

概括 该建议的重点是表征果蝇先天的抗病毒免疫响应。 特别是，对DNA病毒感染的反应，无脊椎动物虹彩病毒6将是 特征。在初步研究中，发现IIV-6感染可诱导 一组JAK-Stat响应性基因称为Turandots或Tot基因。八个小孩 基因编码一个迅速发展的，小的，分泌的蛋白质，没有已知功能。 病毒引起的TOT表达需要病毒复制，p38b MAPK信号和JAK-STAT 激活。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相关的配体在DNA病毒感染后被上调 p38b依赖性方式。在体内，需要p38b和jak-stat途径 DNA病毒感染的生存。总之，这些数据表明病毒感染导致p38b 激活和随后的分泌未配对细胞因子的产生。 upds又 激活JAK-STAT信号传导以诱导TOT基因表达和其他靶基因。 此外，我们发现DNA病毒感染的细胞产生了固体因素 保护幼稚的细胞免受病毒感染。这种抗病毒活性干扰了两种DNA的感染 和RNA病毒。这是DNA病毒感染在果蝇细胞中诱导广泛的抗病毒态。 鉴于TOT的诱导表达和抗菌胡椒样特征 这些发现导致我们假设病毒诱导的Turandot蛋白作为分泌 抗病毒药。 AIM 1探索TOT作为抗病毒辣椒的潜力，而Aim 2提案 表征和识别DNA诱导的固体抗病毒活性的无偏方法 病毒感染。总之，该项目将探测TOT基因诱导的分子机制 并表征DNA病毒诱导的抗病毒状态。