The Host Genetics of Age-Dependent Susceptibility

摘要 衰老和宿主遗传学在病毒感染的易感性中起着关键作用。在我们的建议中，我们使用 协作杂交（CC），一种新的小鼠遗传资源，探索宿主遗传学如何影响年龄 对感染的依赖性易感性。严重急性呼吸系统综合症冠状病毒（SARS- CoV）是21世纪世纪第一次爆发的病毒，引起了一系列呼吸道感染， 在50岁以上的患者中观察到的疾病。重要的是，衰老易感性在小鼠中是保守的， SARS-CoV感染和疾病增加的模型不是由于老年动物中较高的病毒载量。的 结果表明，宿主反应驱动老年人的不同疾病。然而，年龄依赖的易感性是 在遗传多样的CC群体中不完全保守。筛选11个CC品系， 在18个月大的SARS-CoV感染中，我们发现七个品系随着年龄的增长疾病更多，三个品系 与年轻的对照组相当，随着年龄的增长，一个品系的抵抗力更强。我们的初步结果 表明某些遗传因素有助于SARS-CoV感染的年龄依赖性易感性。建筑 从这个屏幕上，我们将产生一个F2杂交使用CC线与年龄相关的敏感性和CC线 没有;然后，我们将挑战年轻和老年F2小鼠，以进一步表征遗传基因座， SARS-CoV疾病，并确定与衰老和年龄依赖性疾病特异相关的QTL。我们 预计这些新的遗传位点将为理解遗传多样性的作用提供基础 在SARS冠状病毒疾病和衰老过程中的作用我们希望这些结果也能为未来的治疗提供信息 老年患者的方法。

Abstract Both aging and host genetics play a critical role in susceptibility to viral infection. In our proposal, we use the Collaborative Cross (CC), a novel mouse genetic resource, to explore how host genetics impacts age dependent susceptibility to infection. Infection with Severe Acute Respiratory Syndrome coronavirus (SARS- CoV), the first outbreak virus of the 21st century, caused a range of respiratory infection with more serve disease observed in patients over the age of 50. Importantly, aging susceptibility is conserved in mouse models of SARS-CoV infection and increased disease is not due to higher viral load in older animals. The results indicate host responses drive differential disease in the aged. However, age-dependent susceptibility is not completely conserved across the genetically diverse CC populations. Screening eleven CC lines with SARS-CoV infection at 18 months old, we identified seven lines with more disease as they aged, three lines equivalent to their younger controls, and one line more resistant as it aged. Together, our preliminary results indicate that certain genetic elements contribute to age-dependent susceptibly to SARS-CoV infection. Building from this screen, we will generate an F2 cross using a CC line with age-dependent susceptibility and a CC line without; we will then challenge both young and aged F2 mice to further characterize genetic loci that contribute to SARS-CoV disease and to identify QTL specifically associated with aging and age-dependent disease. We anticipate that these novel genetic loci will provide a foundation for understanding the role of genetic diversity in SARS-CoV disease and aging processes. We expect the results to also to inform future treatment approaches for elderly patients.