Cutaneous Pathogen-Specific Tissue Resident Memory T Cells in Human Aging

项目摘要 有几条证据表明感染与阿尔茨海默病(AD)的发病机制有关。这 为期一年的补充申请侧重于HSV-1感染的潜在作用。约70%的 老年人感染了HSV-1。亲本R01涉及病毒病原体VZV、带状疱疹、 由于不涉及阿尔茨海默氏症，因此有资格获得补充方案。这个 补充剂与亲本R01有关，因为HSV-1具有相似的致病机理，序列， 和VZV的抗原结构，也因为老化是带状疱疹和 阿尔茨海默氏症。 补充的前提是从解剖学和生物学角度恢复的T细胞的良好特异性 轻度认知障碍(MCI)和阿尔茨海默病的临床相关标本 受试者可以作为生物标志物探针，可能是这些疾病的微生物驱动因素。 单纯疱疹病毒-1与阿尔茨海默病的联系包括阿尔茨海默病与单纯疱疹病毒-1的流行病学联系 APOE4(+)人群的血清阳性、AD组织中HSV-1的检测、HSV-1感染的能力 体外诱导淀粉样蛋白生成及单纯疱疹病毒-1脑感染与人 小鼠模型中的载脂蛋白E基因和痴呆样表型。 研究小组包括HSV-1 T细胞生物学、单细胞T细胞受体方面的专家 人类神经高级组织学的scTCRseq和TCR生物信息学分析 系统组织和轻度认知障碍患者的临床研究。书房就是家- 总部设在华盛顿大学(UW)，包括阿尔茨海默病研究中心 (ADRC)，有一个国内和一个国际协作站点。重要的是，正在进行的NIH UW和每个站点之间存在授予/分包关系，并且PI已发布 每个地点都有多份最近的联合调查员的论文。 目的1从HSV-1阳性MCI患者中回收脑脊液和配血，并用于 湿-LAB和TCRseq干/湿方法确定HSV-1特异性T细胞是否富含 脑脊液与血液的比较。AIM 2从精心策划的AD尸检组织中恢复单个T细胞 荷兰脑库和类似的测量HSV-1特异性。总而言之，目标是 利用T细胞免疫的极端敏感性和记忆特性来检查 假设HSV-1与阿尔茨海默病有关

Project Summary Several lines of evidence link infections to the pathogenesis of Alzheimer’s disease (AD). This one-year Supplement application focuses on the potential role of HSV-1 infection. About 70% of older adults are HSV-1 infected. The parent R01 concerns the viral pathogen VZV, shingles, and aging, and is eligible for the Supplement as does not concern Alzheimer’s Disease. The Supplement is related to the parent R01 because HSV-1 has a similar pathogenesis, sequence, and antigenic structure to VZV, and also because aging is a risk factor for both shingles and Alzheimer’s Disease. The Supplement Premise is that the fine specificity of T cells recovered from anatomically and clinically relevant specimens from Mild Cognitive Impairment (MCI) and Alzheimer’s Disease subjects can be used as a biomarker probe possible microbial driver of these disorders. Linkages between HSV-1 and AD include epidemiologic association of AD with HSV-1 seropositivity in APOE4(+) persons, detection of HSV-1 from AD tissues, the ability of HSV-1 to trigger amyloidogenesis in vitro, and interactions between HSV-1 cerebral infection, human APOE genotype, and dementia-like phenotypes in murine models. The Investigative team includes experts in HSV-1 T cell biology, single cell T cell receptor sequencing (scTCRseq) and TCR bioinformatic analysis, advanced histologic of human nervous system tissue, and the clinical study of Mild Cognitive Impairment subjects. The study is home- based at the University of Washington (UW) including the Alzheimer’s Disease Research Center (ADRC), with one domestic and one international collaborative site. Importantly, ongoing NIH grant/subcontract relationships exist between UW and each site and the PI has published multiple recent papers with the Co-Investigators at each site. Aim 1 recovers CSF and matched blood from HSV-1-seropositive persons with MCI and uses wet-lab and TCRseq dry/wet methods to determine if HSV-1-specific T cells are enriched in CSF compared to blood. Aim 2 recovers single T cells from curated AD autopsy tissues from the Netherlands Brain Bank and similarly measures HSV-1 specificity. Together, the Aims leverage the extreme sensitivity and memory characteristics of T cell immunity to examine the hypothesis that HSV-1 is involved in Alzheimer’s Disease