Genetic Analysis of Resistance to Viral Infection

尽管在先天免疫的广泛领域取得了令人印象深刻的进展，但我们对宿主对病毒感染的抵抗力的理解仍然是相当初步的。免疫学中很少有学科比这更重要。新出现的病毒有可能杀死数亿人，而长期熟悉的病毒也一再证明了它们的能力。本计划项目提案旨在从最基本的层面推进我们对宿主抗病毒性的理解。它是根据我们在分析先天免疫方面的集体经验写成的。我们相信任何试图破解先天免疫的尝试都必须包含三个要素。首先，必须有进化的观点。所有现代后生动物的先天免疫系统已经进化了8亿年或更长时间，许多防御系统的关键特征已经被保存下来。在独立的努力揭示哺乳动物中同源途径的重要性之前两年，果蝇中Toll途径的宿主防御功能被认识到。还众所周知，哺乳动物的TNF信号传导途径在某种程度上被果蝇中单独的先天反应途径（Imd）模仿。这项提案旨在加速发现服务于先天免疫的蛋白质，其基础是祖先的功能在一个伟大的进化过程中往往是保守的。 分开第二，必须有一种方法来快速发现宿主抗性所必需的“新”蛋白（本文称为抗性基因组）。经典（“向前”）遗传学，它几乎启发了生物学的每一个方面，将用于这一目的。经典的遗传学分析对于解剖那些仍然知之甚少的现象特别有用。最近在绘图和测序技术方面的进展，以及对小鼠和果蝇基因组的阐明， 基因组它经常揭示的功能，永远无法通过假设或通过应用非遗传发现导向的工具来掌握。第三，必须有一种针对特定基因和测试生殖系突变影响的方法。基因靶向可以快速破译特定蛋白质的功能，其中有充分的理由相信它们参与生物过程。此外，生殖系突变是 这是分析先天免疫的非常可靠的工具，远远超过我们手头上的任何其他工具。在这里，我们详细介绍了一个计划，用于分析遗传性抵抗病毒感染，争取这三个要素。关于宿主对病毒的抵抗力还有很多有待了解，直到最近，宿主检测病毒感染的基本传感机制才开始出现。目前的建议将填补我们关于病毒感染如何被感知，它们的存在如何被感知， 它们在宿主的细胞和组织内和之间传播，以及它们如何被有效地根除。

Despite impressive advances in the broad field of innate immunity, our understanding of host resistance to viral infection remains quite tentative. Few subjects in immunology are more important. Newly emergent viruses have the potential to kill hundreds of millions of people, and long-familiar viruses have repeatedly proven their ability to do so. The present Program Project proposal is intended to advance our understanding of host resistance to viruses at the most fundamental level. It has been written in light of our collective experience in the analysis of innate immunity. We believe that any attempt to decipher innate immunity must incorporate three elements. First, there must be evolutionary perspective. The innate immune system of all present day metazoans has been evolving for 800 million years or more, and key features of numerous defensive system have been conserved. The host defense function of the Toll pathway in Drosophila was recognized two years before independent efforts revealed the importance of homologous pathways in mammals. It is also widely known that the TNF signaling pathways of mammals are, in some measure, mimicked by a separate innate response pathway (Imd) in Drosophila. This proposal aims to accelerate discovery of the proteins that serve innate immunity based on the fact that ancestral functions are often conserved across a great evolutionary divide. Second, there must be a means to the rapid discovery of "new" proteins essential for host resistance (herein described as the resistome). Classical ("forward") genetics, which has enlightened virtually every aspect of biology, will be used for this purpose. Classical genetic analysis is particularly useful for the dissection of phenomena that are still poorly understood. It has been immensely empowered by recent advances in techniques for mapping and sequencing, and by elucidation of the mouse and Drosophila genomes. It often reveals functions that could never be grasped through hypothesis or through application of non-genetic discovery-oriented tools. Third, there must be a means of targeting specific genes and testing the effects of germline mutations. Gene targeting can quickly decipher the function of specific proteins where there is strong reason to believe that they participate in a biological process. Moreover, germline mutations are extremely reliable tools in the analysis of innate immunity: far more so than any other tools that we have at hand. Herein, we detail a plan for the analysis of inherited resistance to viral infection that enlists each of these three elements. Much remains to be learned about host resistance to viruses, and only recently have the essential sensing mechanisms by which the host detects viral infections begun to .emerge. The present proposal will fill existing gaps in our knowledge about how viral infections are sensed, how their presence is communicated both within and among cells and tissues of the host, and how they can be efficiently eradicated.