MECHANISMS OF IMMUNE VULNERABILITY OF THE ELDERLY TO THE WEST NILE VIRUS

老年人对西尼罗河病毒免疫脆弱的机制

• 批准号: 8357751
• 负责人: Klaus J Fruh
• 金额: $ 0.1万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357751
• 关键词: Age; Arizona; Bioterrorism; CD8B1 gene; Cohort Studies; Data; Defect; Elderly; Funding; Grant; Human; Immune; Immunity; Louisiana; Macaca mulatta; Manuscripts; Modeling; Monkeys; Mus; National Center for Research Resources; Oregon; Pennsylvania; Phenotype; Population; Predictive Value; Predisposition; Primates; Principal Investigator; Reporting; Research; Research Infrastructure; Resistance; Resources; Site; Source; Sum; Testing; Texas; United States National Institutes of Health; Vaccines; Virus; Virus Diseases; West Nile virus; age related; base; cost; multidisciplinary; nonhuman primate; pathogen

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The emerging pathogen and class B agent West Nile virus (WNV), against which there is no approved human vaccine, is especially deadly to the elderly population, for reasons incompletely understood at the present. This proposal will define the underlying mechanism(s) of vulnerability by employing an initially broad, but subsequently more focused, examination of the sum of age- and virus-induced changes in anti-WNV immunity in a succession of mouse, monkey and human models. It is anticipated that one or more mechanisms of age-related vulnerability to WNV and, potentially (in conjunction with our concurrent studies in antipoxvirus immunity in the elderly) to other agents of bioterrorism, will be defined and/or postulated for definitive testing and correction. Specific objectives are to: 1. Establish correlates of WNV protective immunity and define mechanisms of vulnerability to WNV in old mice; 2. Based upon #1, use Rhesus macaque (RM) WNV infection to study vulnerability and resistance to WNV in old non-human primates; 3. Using data from 1&2 and direct tests, define the "immunological age" in elderly humans, evaluate the predictive value of this phenotype for WNV susceptibility and validate key mechanisms of immune vulnerability to WNV in elderly humans. These objectives will be accomplished by integrated efforts of a synergistic multidisciplinary and multi-institutional team from Arizona, Oregon, Texas (two sites) Louisiana and Pennsylvania. Major advances were achieved in the past project period in describing an exquisite resistance of rhesus macaques to the WNV infection, regardless of age or the CD8+ immune status, and also with regard to correcting many, if not all, of the age-related defects in immune responsiveness. These are reported in the two manuscripts listed below, respectively.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 由于目前尚未完全了解的原因，新兴的病原体和B类西尼罗河病毒（WNV）对未经批准的人类疫苗尤其致命。该提议将通过采用最初广泛但更集中的脆弱性来定义脆弱性的基本机制，对年龄和病毒诱导的抗WNV免疫变化的总和进行了一系列小鼠，猴子和人类模型的变化。可以预料，与年龄相关的WNV脆弱性的一种或多种机制可能（与我们在老年人中的抗氧化病毒免疫方面的并发研究结合使用），将被定义和/或假定用于确定性测试和纠正和校正。具体目标是：1。建立WNV保护性免疫的相关性，并定义旧小鼠中WNV脆弱性的机制； 2。基于＃1，使用恒河猕猴（RM）WNV感染来研究旧非人类灵长类动物中对WNV的脆弱性和抵抗力； 3。使用来自1和2的数据并进行直接测试，定义了老年人的“免疫年龄”，评估了该表型对WNV敏感性的预测价值，并验证老年人对WNV的免疫脆弱性的关键机制。这些目标将通过来自亚利桑那州亚利桑那州，俄勒冈州，德克萨斯州（两个地点）路易斯安那州和宾夕法尼亚州的协同多学科和多机构团队的综合努力来实现。 在过去的项目期间，在描述了恒河猕猴对WNV感染的精致抗药性，无论年龄或CD8+免疫状态如何，以及在免疫反应性中纠正许多（如果不是全部）与年龄相关的缺陷方面，取得了重大进展。这些分别在下面列出的两个手稿中报告。