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 该提案的重点是表征果蝇的先天抗病毒免疫反应。 特别是，对 DNA 病毒、无脊椎动物虹彩病毒 6 感染的反应将是 初步研究发现，IIV-6 感染可诱导 IIV-6 的强烈表达。 一组 JAK-STAT 响应基因，称为 Turandots 或 Tot 基因。 基因编码一系列快速进化的、小型的、功能未知的分泌蛋白。 病毒诱导的 Tot 表达需要病毒复制、p38b MAPK 信号传导和 JAK-STAT 此外，未配对 (UPD) 细胞因子是唯一已知的 JAK-STAT。 与哺乳动物 IL-6 关系较远的配体在 DNA 病毒感染后上调 在体内，p38b 和 JAK-STAT 途径都是 p38b 依赖性的。 DNA 病毒感染后的存活率，这些数据表明病毒感染导致 p38b 的产生。 反过来，分泌的未配对细胞因子的激活和随后的产生。 激活 JAK-STAT 信号传导以诱导 Tot 基因和其他靶基因的表达。 此外，我们发现DNA病毒感染的细胞产生可溶性因子， 这种抗病毒活性会干扰两种 DNA 的感染，从而保护幼稚细胞免受病毒感染。 因此，DNA病毒感染在果蝇细胞中诱导广泛的抗病毒状态。 鉴于 Tots 的诱导表达和抗菌肽样特征， 这些发现使我们认识到病毒诱导的图兰朵蛋白的功能与分泌 目标 1 探索了 Tots 作为抗病毒肽的潜力，而目标 2 提出了一种 表征和鉴定 DNA 诱导的可溶性抗病毒活性的公正方法 总之，该项目将探讨Tot基因诱导的分子机制。 并表征 DNA 病毒诱导的抗病毒状态。