Insect adaptive immunity

昆虫适应性免疫

基本信息

批准号：
10469408
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
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-14 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10469408
关键词：
Address Animal Model 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

项目摘要

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.

概括该项目的中心目标是检查昆虫的抗病毒免疫力，虫媒病毒的昆虫传播。在全球范围内引起广泛的、使人衰弱的疾病，病毒在载体中复制和传播。 RNA干扰是昆虫主要抗病毒系统的关键因素。抑制病毒复制和病毒在整个昆虫组织中的传播。人们对发展和有效的抗病毒免疫力知之甚少。我们建议研究模式生物果蝇的抗病毒免疫力。我们发现这一点。免疫涉及血细胞摄取病毒双链RNA，然后逆转录为生成病毒 DNA (vDNA)，通过从头合成 siRNA 来放大 RNAi 反应（次级 vsRNA）果蝇免疫的核心是巨噬细胞样细胞、血细胞，它们是负责通过产生 5'-三磷酸化二级 vsRNA 进行抗病毒 RNAi 扩增。在效应器表面，vsRNA 被整合到血细胞衍生的 ELV 介导的外泌体样囊泡 (ELV) 中。将抗病毒 vsRNA 递送至未感染的组织并保护果蝇免受远端部位的感染。与脊椎动物惊人地相似，苍蝇也依靠全身免疫来控制病毒感染，尽管在这种情况下在这种情况下，病毒特异性信号是基于核酸的，我们捕获到血细胞从其中摄取 dsRNA。受感染的细胞指导 vDNA 的合成，vDNA 反过来又模板次级 vsRNA，提供适应性我们将研究 (i) vDNA 合成机制，(ii) vsRNA 的产生和调节。 (iii) 抗病毒 ELV 的产生及其在抗病毒免疫中的功能。