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.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 新出现的病原体和B类病原体西尼罗河病毒（WNV）对老年人特别致命，目前还没有批准的人类疫苗。该提案将通过采用最初广泛但随后更集中的方法，在小鼠，猴和人类模型中连续检查年龄和病毒诱导的抗WNV免疫力变化的总和，来定义脆弱性的潜在机制。预计将定义和/或假设一种或多种与年龄相关的易受西尼罗河病毒感染的机制，并可能（与我们在老年人抗痘病毒免疫方面的同步研究相结合）对其他生物恐怖主义分子的易感性进行明确的检测和纠正。具体目标是：1.建立老年小鼠西尼罗河病毒保护性免疫的相关性，明确老年小鼠对西尼罗河病毒易感性的机制。在#1的基础上，利用恒河猴（RM）感染WNV研究老年非人灵长类动物对WNV的易感性和抗性;使用来自1&2和直接测试的数据，定义老年人的“免疫年龄”，评估该表型对WNV易感性的预测价值，并验证老年人对WNV免疫脆弱性的关键机制。这些目标将通过来自亚利桑那州、俄勒冈州、得克萨斯州（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小组的综合努力来实现。 在过去的项目期间，在描述恒河猴对WNV感染的精致抗性方面取得了重大进展，无论年龄或CD 8+免疫状态如何，并且在纠正许多（如果不是全部）与年龄相关的免疫反应缺陷方面也取得了重大进展。这些都是在下面列出的两个手稿分别报告。