Genetic Analysis of Resistance to Viral Infection

尽管在广泛的先天免疫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相当试探性的。免疫学中没有几门学科比这更重要。新出现的病毒有可能导致数亿人死亡，而熟悉已久的病毒一再证明它们有能力做到这一点。本计划项目提案的目的是在最基本的水平上促进我们对宿主对病毒抵抗力的理解。它是根据我们在分析先天免疫方面的集体经验编写的。我们认为，任何破译先天免疫的尝试都必须包含三个要素。首先，必须有进化论的观点。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一直被保存下来。在独立研究揭示同源通路在哺乳动物中的重要性之前两年，果蝇Toll通路的宿主防御功能就被认识到了。众所周知，哺乳动物的肿瘤坏死因子信号通路在某种程度上是由果蝇的一个单独的先天反应途径(IMD)模仿的。这一建议旨在加速发现具有先天免疫功能的蛋白质，这一事实基于这样一个事实，即祖先的功能在一次伟大的进化过程中往往是保守的。 分头行动。其次，必须有一种方法来快速发现寄主抗性所必需的“新”蛋白质(在这里被描述为抗药性)。经典(“前沿”)遗传学实际上已经启发了生物学的方方面面，它将被用于这一目的。经典的遗传分析对于剖析仍然知之甚少的现象特别有用。最近在测绘和测序技术上的进步，以及对小鼠和果蝇的阐明，极大地增强了它的能力 基因组。它往往揭示了永远不能通过假说或非基因发现导向工具的应用来掌握的功能。第三，必须有一种针对特定基因并测试种系突变效果的方法。基因打靶可以迅速破译特定蛋白质的功能，在这些蛋白质中，有很强的理由相信它们参与了生物过程。此外，生殖系突变是 在分析先天免疫方面极其可靠的工具：比我们手头的任何其他工具都要可靠得多。在这里，我们详细介绍了一项分析遗传的病毒感染抵抗力的计划，该计划包括了这三个要素。关于宿主对病毒的抵抗力还有许多需要了解的地方，直到最近，宿主检测病毒感染的基本传感机制才开始出现。目前的提议将填补我们关于病毒感染是如何被感知的、它们的存在是如何存在的现有知识的空白 在寄主的细胞和组织内和之间传播，以及如何有效地根除它们。

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.