Rapid Induction of apoptosis against viral infection

节肢动物传播的病原体每年造成数百万人死亡。了解 病原体易感性的遗传基础是新的疾病控制的关键 战略。认为诱导细胞凋亡是一种基本的先天免疫的假设 反应得到了病毒学研究的支持，这些研究表明，抗- 许多病毒基因的凋亡活性对它们的传染性和/或毒力是必不可少的。 然而，介导病毒诱导细胞凋亡的细胞机制 感染仍然是个谜。此外，对培养的昆虫细胞的研究表明， 要么是缺乏凋亡，要么是促凋亡反应发生得相对较晚， 令人怀疑细胞凋亡作为一种先天免疫的功能意义。vbl.使用 在模拟天然病毒感染途径的体内蚊子模型中，我们发现有 在接下来的几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，利用果蝇的基因工具，我们 表明RIPAG和随之而来的细胞凋亡，是否认 病毒基因的表达和阻断/限制感染。动物受到危害 RIAPG比野生型更容易受到病毒感染。在这项提案中，我们 寻求解开转录机制和调控途径(S) 利用果蝇遗传学和比较遗传技术相结合控制RIPAG 基因组学。此外，利用通过机械学获得的信息 分析，我们将检验提高对病毒的天然免疫力的假设 感染可以通过增强RIPAG对病毒感染的反应来实现。最后， 我们评估我们在果蝇体内创建的抗病毒结构的适合性，然后翻译 最强大和最合适的构建两个蚊子媒介并执行 转基因抗登革热效果的初步评价。

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.