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 病媒对病原体易感性的遗传基础是新型疾病控制的关键 战略布局细胞凋亡的诱导是一种基本的先天免疫的假说 病毒学研究支持了这种反应，研究表明， 许多病毒基因的凋亡活性对于它们的感染性和/或毒力是必需的。 然而，介导病毒感染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， 或者缺乏凋亡，或者促凋亡反应发生相对较晚， 这对细胞凋亡作为先天免疫的功能意义提出了质疑。使用 在模拟病毒感染的天然途径的体内蚊子模型中，我们发现 促凋亡基因（RIPAG）的快速诱导在几个小时内， 接触DNA/RNA病毒。更重要的是，在果蝇中使用遗传工具， 表明RIPAG和随之而来的细胞凋亡是否认细胞凋亡的原因。 病毒基因的表达和阻断/限制感染。受损动物 RIAPG比野生型更易受病毒感染。在本提案中，我们 试图解开转录机制和调控途径 控制RIPAG使用果蝇遗传学和比较的组合， 基因组学此外，利用通过机械获得的信息， 分析，我们将测试的假设，增加先天免疫力对病毒 感染可以通过增强RIPAG对病毒感染的应答来实现。最后， 我们评估我们在果蝇中创造的抗病毒结构的适应性， 最强大和最适合的构建体的两个蚊子载体，并执行 转基因对登革热有效性的初步评估。

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.