Rapid Induction of apoptosis against viral infection

快速诱导细胞凋亡对抗病毒感染

• 批准号: 8631806
• 负责人: Lei Zhou
• 金额: $ 28.41万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8631806
• 关键词: Accounting; Animals; Antiviral Agents; Apoptosis; Apoptotic; Arthropods; Budgets; Cells; Cessation of life; Culicidae; DNA; Dengue; Disease; Drosophila genus; Effectiveness; Elements; Evaluation; Exposure to; Funding; Genes; Genetic; Genetic Transcription; Genomics; Hour; Human Resources; Immune response; Induction of Apoptosis; Infection; Insecta; Knowledge; Mediating; Modeling; Natural Immunity; Predisposition; RNA Interference; RNA Viruses; Regulatory Pathway; Route; Signal Pathway; Testing; TimeLine; Transgenes; Translating; Uncertainty; Viral Genes; Virulence; Virus Diseases; base; combat; comparative genomics; disorder control; fitness; in vivo; novel; pathogen; public health relevance; research study; response; tool; vector; vector control; vector mosquito; virology

Arthropod-borne pathogens account for millions of death each year. Understanding the genetic basis of vector susceptibility to pathogens is pivotal to novel disease control strategies. The hypothesis that induction of apoptosis is a fundamental innate immune response has been supported by virology studies, which demonstrated that the anti- apoptotic activities of many viral genes are essential for their infectivity and/or virulence. However, the cellular mechanism mediating the induction of apoptosis following virus infection remained enigmatic. In addition, studies with cultured insect cells showed that either there is a lack of apoptosis, or the pro-apoptotic response happens relatively late, casting doubt on the functional significance of apoptosis as an innate immunity. Using in vivo mosquito models mimicking native routes of viral infection, we found that there is a rapid induction of pro-apoptotic genes (RIPAG) within a few hours following exposure to DNA/RNA viruses. More importantly, using genetic tools in Drosophila, we showed that the RIPAG, and the ensuing apoptosis, is responsible for denying the expression of viral genes and blocking/limiting the infection. Animals with compromised RIAPG are much more susceptible to viral infection than wild type. In this proposal, we seek to unravel the transcriptional mechanisms and the regulatory pathway(s) controlling RIPAG using a combination of Drosophila genetics and comparative genomics. In addition, utilizing the information obtained through the mechanistic analysis, we will test the hypothesis that increased innate immunity against viral infection may be achieved by enhancing the RIPAG response to viral infection. Finally, we assess the fitness of the antiviral constructs we create in Drosophila, then translate the most powerful and most fit constructs to two mosquito vectors and perform preliminary evaluations of transgene effectiveness against Dengue.

节肢动物传播的病原体每年死亡数百万。了解 载体对病原体敏感性的遗传基础对新型疾病控制至关重要 策略。诱导凋亡是一种基本先天免疫的假设 病毒学研究支持了反应，这表明抗 许多病毒基因的凋亡活性对于它们的感染性和/或毒力至关重要。 然而，病毒后介导凋亡诱导的细胞机制 感染仍然是神秘的。此外，对培养昆虫细胞的研究表明 缺乏凋亡，或者促凋亡反应发生相对较晚， 对凋亡作为先天免疫的功能意义提出怀疑。使用 体内蚊子模型模仿了病毒感染的天然途径，我们发现有 在几个小时内快速诱导促凋亡基因（RIPAG） 暴露于DNA/RNA病毒。更重要的是，使用果蝇中的遗传工具，我们 表明RIPAG和随后的凋亡是否认 病毒基因的表达并阻塞/限制感染。动物被妥协 与野生型相比，RIAPG更容易受到病毒感染的影响。在这个建议中，我们 寻求揭开转录机制和调节途径 使用果蝇遗传学和比较的组合来控制RIPAG 基因组学。另外，利用通过机械获得的信息 分析，我们将检验以下假设，即对病毒的先天免疫力增加 可以通过增强对病毒感染的RIPAG反应来实现感染。最后， 我们评估我们在果蝇中创建的抗病毒构建体的适应性，然后翻译 两个蚊子载体最强大，最合适的结构，并表演 对登革热的转基因有效性的初步评估。