Developing Anti-viral Ribozymes to Suppress Arboviruses in Transgenic Mosquitoes

开发抗病毒核酶来抑制转基因蚊子中的虫媒病毒

• 批准号: 8581314
• 负责人: Malcolm J. FRASER
• 金额: $ 56.3万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8581314
• 关键词: Aedes; Affect; Alphavirus; Antisense Oligonucleotides; Antiviral Agents; Apoptosis; Arbovirus Infections; Arboviruses; Arthropod Vectors; Attention; Catalytic RNA; Cell Culture Techniques; Cells; Cessation of life; Cleaved cell; Climate; Commerce; Conserved Sequence; Coupled; Culicidae; DNA Polymerase III; Dengue; Disease; Double-Stranded RNA; Drug resistance; Effectiveness; Ensure; Enzymes; Exons; Flavivirus; Genes; Genetic; Genome; Goals; Health; Hepatitis D; Human; Immunization; Infection; Insecta; Introns; Mediating; Population; Population Replacements; Public Health; RNA; RNA Interference; Refractory; Research; Resistance; Safety; Testing; Time; Transgenes; Transgenic Organisms; Travel; Urbanization; Vaccines; Viral; Virus; Virus Diseases; Yellow Fever; chikungunya; cost effectiveness; disease transmission; hammerhead ribozyme; improved; novel strategies; pathogen; prevent; programs; success; transgene expression; transmission process; vaccination strategy; vector; vector control; vector mosquito

DESCRIPTION (provided by applicant): Chikungunya (CHIKV), yellow fever (YFV), and Dengue (DENV) are among the most troublesome human health pathogens responsible for hundreds of millions of infections and hundreds of thousands of deaths each year. They are transmitted to human populations by a single mosquito species, Aedes aegypti. Effective human vaccines are not yet available for CHIK, and DENV, and the re-emergence of YFV as a lethal pathogen, in spite of the availability of an effective vaccine, suggests ineffectiveness of vaccination strategies for sustained eradication. Interference with the incubation arboviruses within the arthropod vector is receiving considerable attention as a way to interrupt the viral transmission cycle and reduce the efficiency of transmission to humans. One such approach envisions population replacement of susceptible mosquitoes with those resistant to infection or to halt disease transmission. This approach has distinct advantages of environmentally safety, cost effectiveness, and long-term disease suppression. Transgenic introduction of expressed anti-viral molecules to generate refractoriness in the mosquito vector is now a real possibility. Recent successes reflected in the RIDL approach show significant promise, and can reasonably be expected to be coupled with transgenic refractoriness to establish and maintain transgene effectors in rebound mosquito populations. However, this avenue must necessarily be coupled with ensuring both long term effectiveness and stable transgene expression. Our research is demonstrating that ribozyme (RNA-enzyme) mediated viral suppression can provide an effective means of transgenic immunization against viruses. Recent efforts have confirmed the effectiveness of hammerhead ribozymes and Group I introns in suppressing DENV infection in mosquito cells. The research proposed seeks to build upon our successes in developing anti-viral ribozymes as potent effector genes against arbovirus infections in mosquitoes. In particular, this proposal will focus on developing, optimizing, and validating effective ribozyme suppression strategies against three major emerging and re-emerging disease pathogens vectored by the same mosquito species, Aedes aegypti, DENV, CHIKV, and YF. The ultimate goal is to be able to provide mosquito strains that will be useful in simultaneously eliminating two or more of these viral diseases.

描述（由申请人提供）：基孔肯雅热（CHIKV）、黄热病（YFV）和登革热（DENV）是最麻烦的人类健康病原体，每年导致数亿人感染和数十万人死亡。它们通过一种蚊子——埃及伊蚊传播给人类。目前还没有针对 CHIK 和 DENV 的有效人类疫苗，并且尽管有有效疫苗，但 YFV 作为致命病原体重新出现，表明持续根除疫苗接种策略的无效性。干扰节肢动物载体内孵化的虫媒病毒作为中断病毒传播周期和降低向人类传播的效率的一种方法受到了相当多的关注。其中一种方法设想用抗感染或阻止疾病传播的蚊子取代易感蚊子。该方法具有环境安全、成本效益和长期疾病抑制的明显优势。现在确实有可能通过转基因引入表达的抗病毒分子来在蚊子载体中产生耐药性。 RIDL 方法最近取得的成功显示出巨大的前景，并且可以合理地预期其与转基因耐药性相结合，以在反弹的蚊子种群中建立和维持转基因效应子。然而，这种途径必须同时确保长期有效性和稳定的转基因表达。我们的研究表明，核酶（RNA 酶）介导的病毒抑制可以提供针对病毒的转基因免疫的有效手段。最近的研究证实了锤头核酶和 I 类内含子在抑制蚊子细胞中 DENV 感染方面的有效性。拟议的研究旨在以我们开发抗病毒核酶作为对抗蚊子虫媒病毒感染的有效效应基因的成功为基础。特别是，该提案将侧重于开发、优化和验证针对由同一蚊种（埃及伊蚊、DENV、CHIKV 和 YF）传播的三种主要新出现和重新出现的疾病病原体的有效核酶抑制策略。最终目标是能够提供可用于同时消除两种或多种这些病毒性疾病的蚊子菌株。