Insect adaptive immunity

昆虫适应性免疫

• 批准号: 10239093
• 负责人: Raul Andino
• 金额: $ 50.73万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-14 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10239093
• 关键词: Address; Animal Model; Antiviral Agents; Antiviral Response; Arboviruses; Biogenesis; Biological Assay; Blood Circulation; Cells; Competence; Complementary DNA; Cultured Cells; DNA amplification; DNA biosynthesis; DNA-Directed RNA Polymerase; Data; Defense Mechanisms; Dengue; Disease; Distal; Double-Stranded RNA; Drosophila genus; Drosophila melanogaster; Face; Generations; Genetic Transcription; Genome; Goals; Hemocytes; Human; Immune response; Immune system; Immunity; Immunologic Memory; Infection; Insect Vectors; Insecta; Lead; Mediating; Medical; Methods; Nucleic Acids; Organism; Passive Immunization; Pathogenicity; Pathway interactions; Physiology; Process; Production; Proteomics; RNA; RNA Interference; RNA chemical synthesis; RNA-Directed DNA Polymerase; Regulation; Reverse Transcription; Role; Signal Transduction; Site; Small Interfering RNA; Small RNA; System; Testing; Tissues; Transcript; Vertebrates; Vesicle; Viral; Virus; Virus Diseases; Virus Replication; ZIKA; adaptive immunity; antiviral immunity; base; chikungunya; design; exosome; fly; functional genomics; insight; macrophage; programs; recruit; response; transmission process; tripolyphosphate; uptake; vector; viral DNA; viral RNA

SUMMARY The central goal of this project is to examine antiviral immunity in insects. Insect transmission of arboviruses causes widespread and debilitating disease across the globe. Viral replication and dissemination in the vector are critical factors in transmission competence. RNA interference is the insect major antiviral system that inhibits viral replication and viral dissemination throughout the insect tissues. The mechanisms involved in developing and effective antiviral immunity are poorly understood. We propose to study antiviral immunity in the model organism Drosophila melanogaster. We discovered that immunity involves uptake of viral double stranded RNA by hemocytes, followed by reverse transcription to generate viral DNAs (vDNAs) that enables amplification of the RNAi response by de novo synthesis of siRNAs (secondary vsRNAs). Central to Drosophila immunity are macrophage-like cells, hemocytes, which are responsible for antiviral RNAi amplification by the production of 5’-triphosphorylated secondary vsRNAs. In the effector face, vsRNAs are incorporated into exosome-like vesicles (ELVs). Haemocyte-derived ELVs mediate the delivery of antiviral vsRNAs to uninfected tissues and protect flies from infection at distal sites. In striking parallel to vertebrates, flies also rely on systemic immunity to control viral infection, albeit in this case the virus-specific signal is nucleic acid-based. We hypothesize that haemocytes take up dsRNA from infected cells to direct the synthesis of vDNA, which in turn templates secondary vsRNA providing adaptive immunity. We will examine (i) the mechanisms of vDNA synthesis, (ii) production and regulation of vsRNA production and (iii) the generation of antiviral ELVs and their function in antiviral immunity.

总结 这个项目的中心目标是研究昆虫的抗病毒免疫。虫媒病毒的昆虫传播 在地球仪上引起广泛传播的使人衰弱的疾病。病毒在载体中复制和传播 是传输能力的关键因素。RNA干扰是昆虫主要的抗病毒系统， 抑制病毒在昆虫组织中的复制和传播。涉及的机制 发展和有效的抗病毒免疫力知之甚少。 我们建议在模式生物果蝇中研究抗病毒免疫。我们发现 免疫包括血细胞摄取病毒双链RNA，然后逆转录， 产生病毒DNA（vDNA），其能够通过siRNAs的从头合成来扩增RNAi应答 （次级vsRNA）。果蝇免疫的核心是巨噬细胞样细胞，血细胞， 通过产生5 '-三磷酸化的二级vsRNA负责抗病毒RNAi扩增。在 在效应面，vsRNA被掺入外泌体样囊泡（ELV）中。血细胞来源的ELV介导 将抗病毒vsRNA递送到未感染的组织，并保护苍蝇免受远端部位的感染。 与脊椎动物惊人的相似，苍蝇也依赖于全身免疫来控制病毒感染，尽管在这种情况下， 在病毒特异性信号是基于核酸的情况下。我们假设血细胞摄取dsRNA来自 感染的细胞来指导vDNA的合成，vDNA又以次级vsRNA为模板，提供适应性的 免疫力我们将研究（i）vDNA合成的机制，（ii）vsRNA的产生和调节， 生产和（iii）抗病毒ELV的产生及其在抗病毒免疫中的功能。