Chronic CMV infection in the elderly: diagnosis and link to chronic inflammation

描述（由申请人提供）：来自我们和其他人的大量证据表明，以IL-6升高为标志的慢性炎症状态导致老年人中许多与年龄相关的疾病、虚弱、残疾和死亡。尽管如此，导致这种慢性炎症状态的原因和潜在机制仍有待确定。研究报道了巨细胞病毒（CMV）特异性T细胞在CMV血清阳性老年人中的克隆扩增，以及CMV血清阳性或绝对滴度与虚弱、残疾和死亡率的相关性。然而，文献中存在大量冲突报告。这是因为抗CMV IgG血清学是一种粗略的测量方法，仅表明先前暴露于病毒，并没有区分过去（解决）或慢性（持续）感染。CMV生物学表明，虽然大多数人都暴露于病毒，但CMV可以在一些人中持续存在，病毒基因组（DNA）存在于外周血单核细胞中，代表慢性感染。本申请旨在表征通过基于巢式PCR的测定法检测的单核细胞中的CMV病毒DNA，并检验单核细胞中的CMV DNA比抗CMV IgG血清学更好地预测老年人中的T细胞免疫衰老和慢性炎症的假设。我们将在妇女健康与老龄化研究II中进行深入的纵向分析，这是一项由NIA资助的大型队列研究，在12年的7次访视中收集了外周血单个核细胞（PBMC）和血清。我们的假设得到了我们已发表的初步研究的支持，即只有约50%-60%的CMV血清阳性老年人的单核细胞中有CMV DNA，CMV DNA（而不是IgG滴度）与CMV特异性CD 8 T细胞增加和血清新蝶呤和IL-6水平升高相关。在相隔12年的两个时间点的初步数据显示，CMV DNA状态随时间的变化与CMV特异性CD 8 T细胞和IL-6水平的变化平行，而抗CMV IgG滴度保持不变。我们提出两个目标：1）检验抗CMV IgG血清学不能预测老年人单核细胞中CMV DNA随时间的存在和变化的假设，以及2）检验单核细胞中CMV DNA比抗CMV IgG血清学更能预测以下情况的假设：a）通过CMV特异性和产生干扰素（IFN）-g的CD 8 T细胞和终末分化的T细胞亚群的扩增测量的T细胞免疫衰老（CD 28-、CD 27-和CD 45 RA+），和B）升高的IL-6和新蝶呤水平。获得的数据将最终使我们能够建立慢性CMV感染与T细胞免疫衰老和慢性炎症之间的联系。如果我们的假设得到证实，这些数据将为进一步研究慢性巨细胞病毒感染导致老年人出现不良健康结果的基本免疫和炎症机制开辟新的研究途径，这将通过包括R在内的其他资助机制进行。01。主要的健康影响包括通过预防或减轻慢性CMV感染及其对这一脆弱人群的免疫力和健康的不利影响，促进成功衰老和维持功能。

DESCRIPTION (provided by applicant): A large body of evidence from us and others indicates that a chronic inflammatory state marked by elevated IL-6 contributes to many age-related diseases, frailty, disability and mortality in older adults. Despite this, the causes and underlying mechanisms leading to this chronic inflammatory state remain to be defined. Studies have reported clonal expansion of cytomegalovirus (CMV)-specific T cells in CMV-seropositive older persons and associations of CMV seropositivity or absolute titers with frailty, disability, ad mortality. However, ample conflict reports exist in the literature. This is because anti-CMV IgG serology is a crude measure that merely indicates prior exposure to the virus and makes no distinction between past (resolved) or chronic (persistent) infections. CMV biology indicates that while most people are exposed to the virus, CMV can persist in some with the viral genome (DNA) harbored in peripheral blood monocytes, representing a chronic infection. This application seeks to characterize CMV viral DNA in monocytes detected by a nested PCR-based assay and test the hypothesis that CMV DNA in monocytes predicts T-cell immunosenescence and chronic inflammation in older adults better than anti-CMV IgG serology. We will use an in-depth longitudinal analysis in the Women's Health and Aging Studies II, a large NIA-funded cohort study with banked peripheral blood mononuclear cells (PBMCs) and sera collected at 7 visits over 12 years. Our hypothesis is supported by our published pilot studies that only about 50%-60% of CMV-seropositive older persons had CMV DNA in monocytes and that CMV DNA (and not IgG titer) was associated with increased CMV-specific CD8 T cells and elevated serum neopterin and IL-6 levels. Preliminary data at two time points 12 years apart shows change in CMV DNA status over time in parallel with that in CMV-specific CD8 T cells and IL-6 levels, while anti-CMV IgG titer remains the same. We propose two aims: 1) To test the hypothesis that anti-CMV IgG serology does not predict the presence and change of CMV DNA in monocytes in older adults over time, and 2) To test the hypothesis that CMV DNA in monocytes is a better predictor than anti-CMV IgG serology for: a) T-cell immunosenescence as measured by expansion of CMV-specific and interferon (IFN)-g-producing CD8 T cells and terminally differentiated T-cell subsets (CD28-, CD27-, and CD45RA+), and b) elevated IL-6 and neopterin levels. The data obtained will ultimately enable us to establish a link between chronic CMV infection and both T-cell immunosenescence and chronic inflammation. If our hypotheses are confirmed, this data will open new research avenues for further studies into fundamental immunological and inflammatory mechanisms by which chronic CMV infection contributes to the development of adverse health outcomes in older adults, which will be pursued via other funding mechanisms including R01. Major health implications include fostering successful aging and maintaining function through prevention or mitigation of chronic CMV infection and its adverse impact on immunity and health for this vulnerable population.