The Host Genetics of Age-Dependent Susceptibility

年龄依赖性易感性的宿主遗传学

• 批准号: 10007171
• 负责人: VINEET D MENACHERY
• 金额: $ 24.59万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10007171
• 关键词: Age; Aging; Animals; Automobile Driving; Breathing; Candidate Disease Gene; Case Fatality Rates; Cause of Death; Chromosome Mapping; Communicable Diseases; Coronavirus Infections; Data; Disease; Disease Outbreaks; Disease Outcome; Elderly; Family; Foundations; Functional disorder; Future; Genes; Genetic; Genetic Structures; Genetic Variation; Goals; Health; Immune response; Immunity; Inbred Strains Mice; Infection; Influenza A virus; Link; Maps; Mediating; Mus; Outcome; Pathogenesis; Patients; Phenotype; Play; Population; Population Heterogeneity; Predisposition; Process; Quantitative Trait Loci; Resistance; Respiratory Tract Infections; Role; SARS coronavirus; Severe Acute Respiratory Syndrome; Time; Treatment outcome; Tumor-infiltrating immune cells; Variant; Viral Load result; Virus; Virus Diseases; age related; aged; chikungunya; genetic element; genetic resource; genomic locus; immune function; improved; insight; mortality; mouse genetics; mouse model; novel; older patient; phenotypic data; population based; screening; senescence; validation studies

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.

摘要 衰老和宿主遗传都在病毒感染的易感性中起着关键作用。在我们的提案中，我们使用 协作杂交(CC)，一种新的小鼠遗传资源，以探索宿主遗传学如何影响年龄 对感染的依赖易感性。感染严重急性呼吸系统综合症冠状病毒(SARS- 冠状病毒)，21世纪的第一次暴发病毒，引起了一系列更严重的呼吸道感染 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冠状病毒感染和疾病增加的模型并不是由于老年动物的病毒载量较高。这个 结果表明，宿主反应驱动了老年人的辨证疾病。然而，年龄相关的易感性是 在遗传多样性的CC种群中并不完全保守。对11个CC品系的筛选 在18个月龄时感染SARS冠状病毒，我们发现有7个品系随着年龄的增长疾病更多，3个品系 相当于他们年轻的对照组，随着年龄的增长，一种更具抵抗力的品系。总而言之，我们的初步结果 提示某些遗传因素与年龄相关的SARS冠状病毒感染易感性有关。建房 在此屏幕上，我们将使用具有年龄相关感受性的CC系和CC系生成F2杂交 然后，我们将挑战年轻和老年的F2小鼠，以进一步表征导致 寻找与SARS冠状病毒病相关的QTL以及与衰老和年龄相关疾病相关的QTL。我们 预计这些新的遗传基因座将为理解遗传多样性的作用提供基础 在SARS冠状病毒病和衰老过程中。我们希望这一结果也能为未来的治疗提供参考。 老年患者的治疗方法。