Temporal responses in host-virus interactions

项目摘要 除了患慢性病的风险更高外，老年人更容易受到伤害， 比年轻的成年人感染传染病，包括病毒感染，往往表现出更高的发病率，严重程度， 和死亡率。尽管在理解病毒与它们之间的相互作用方面取得了许多进展， 作为东道主，我们缺乏关于这些关系作为年龄函数的基础过程的知识。与 由于地球上老年人的人数空前，一个主要目标是确保适当的预防和 治疗策略带来更长、更健康的生活。因此，非常需要解开 这是老年机体抵抗感染的基本机制。 在本申请中，我们建议使用模式生物黑腹果蝇（Drosophila melanogaster）来研究 这些机制有助于RNA病毒感染的年龄依赖性存活。准确地说，我们将使用 结合遗传和分子方法，1）研究炎症性NF-kB通路的作用 在与老年病毒感染相关免疫病理学中，2）对一组 进化上保守的基因，以前没有报道过在抗病毒免疫中的作用。我们的实验将集中在 研究感染耐受机制作为年龄依赖性抗病毒防御策略的作用。我们将 我们还试图确定进化上保守的NF-kB炎症通路和可能的其他细胞因子是如何影响炎症反应的。 这些途径与老年宿主在病毒感染后存活的能力受损有关。会来做这项工作 研究了果蝇IMD NF-κ B的几种突变体中感染的年龄依赖性结果， kB途径和新的候选基因被敲低或过表达的果蝇品系。因为 我们预计，从苍蝇到人类，潜在的遗传和分子机制可能是保守的。 这些研究提供了重要的新见解，填补了有关病毒相互作用的知识空白， 他们的老主人我们的研究可能会导致未来对感染老年人的治疗改进 患者拟议的项目也有一个目标，即招募和培养一批多样化的学生， 代表科学，技术，工程和数学（STEM）的下一代学者。

PROJECT SUMMARY In addition of being at higher risk for developing chronic disease, elderly individuals are more vulnerable than younger adults to infectious diseases, including viral infections, and often exhibit higher incidence, severity and mortality rates. Despite numerous advances in understanding the interactions between viruses and their hosts, we lack knowledge about the processes underlying these relationships as a function of age. With the unprecedented numbers of older individuals on the planet, a major goal is to ensure appropriate preventive and treatment strategies leading to a longer, healthier life. Consequently, there is great need to unravel the fundamental mechanisms that lie beneath the capability of the aged organism to survive infection. In this application, we propose to use the model organism Drosophila melanogaster to investigate the mechanisms that contribute to age-dependent survival of infection with an RNA virus. Precisely, we will use a combination of genetic and molecular approaches to 1) investigate the role inflammatory NF-kB pathways play in immunopathology associated with viral infection at older age 2) conduct functional analysis of a set of evolutionarily conserved genes with no previously reported role in antiviral immunity. Our experiments will focus on studying the role of infection tolerance mechanisms as an age-dependent anti-viral defense strategy. We will also seek to determine how the evolutionarily conserved NF-kB inflammatory pathway and possibly other cellular pathways are implicated in the impaired ability of the older host to survive virus infection. This will be done by examining age-dependent outcomes of infection in several mutants for components of the Drosophila IMD NF- kB pathway and in fly lines in which novel candidate genes are being knocked down or overexpressed. Because the underlying genetic and molecular mechanisms are likely to be conserved from flies to humans, we expect these studies to provide important new insights filling the knowledge gap about the interactions of viruses and their older hosts. Our studies could potentially lead to future therapeutic improvements for infected elderly patients. The proposed project also has for a goal to recruit and train a diverse body of students who will represent the next generation of scholars in the science, technology, engineering, and mathematics (STEM).