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

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 西尼罗河病毒(WNV)是一种新出现的病原体和B类病原体，目前还没有获得批准的人类疫苗，它对老年人口尤其致命，原因目前尚不完全清楚。这项建议将通过使用一种最初广泛但随后更有针对性的研究，在一系列小鼠、猴子和人类模型中，对年龄和病毒诱导的抗西尼罗病毒免疫变化的总和进行检查，从而定义脆弱性的潜在机制(S)。预计将定义和/或假设一个或多个与年龄相关的易受西尼罗河病毒和潜在(结合我们在老年人中的抗痘病毒免疫)其他生物恐怖主义制剂的易感性的机制，以进行明确的测试和纠正。具体目标是：1.建立WNV保护性免疫的相关性并确定老年小鼠对WNV的易感性机制；2.在#1的基础上，利用恒河猴(RM)WNV感染研究老年非人类灵长类动物对WNV的易感性和抵抗力；3.利用1和2的数据和直接试验的数据，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免疫易感性的关键机制。这些目标将通过来自亚利桑那州、俄勒冈州、德克萨斯州(路易斯安那州和宾夕法尼亚州两个地点)的多学科和多机构协同团队的综合努力来实现。 在过去的项目期间，在描述恒河猴对西尼罗河病毒感染的精致抵抗力方面取得了重大进展，无论年龄或CD8+免疫状态如何，在纠正免疫反应中与年龄相关的许多缺陷方面也取得了重大进展。这些分别在下面列出的两份手稿中得到了报道。

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.