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造成数百万人死亡。理解