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明确。研究报道了巨细胞病毒（CMV）特异性T细胞在巨细胞病毒血清阳性的老年人中克隆扩增，以及巨细胞病毒血清阳性或绝对滴度与虚弱、残疾和死亡率的关联。然而，文献中存在大量的冲突报道。这是因为抗巨细胞病毒IgG血清学是一种粗略的测量方法，仅表明先前暴露于病毒，无法区分过去（已解决）或慢性（持续）感染。巨细胞病毒生物学表明，虽然大多数人暴露于病毒，巨细胞病毒可以持续存在于一些病毒基因组（DNA）在外周血单核细胞，代表慢性感染。本应用旨在通过巢式pcr检测单核细胞中巨细胞病毒DNA的特征，并验证单核细胞中巨细胞病毒DNA比抗巨细胞病毒IgG血清学更能预测老年人t细胞免疫衰老和慢性炎症的假设。我们将在妇女健康与衰老研究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年的时间里收集了7次外周血单个核细胞（PBMCs）和血清。我们发表的初步研究支持了我们的假设，即只有约50%-60%的CMV血清阳性老年人单核细胞中有CMV DNA， CMV DNA（而不是IgG滴度）与CMV特异性CD8 T细胞的增加和血清中新蛋白和IL-6水平的升高有关。相隔12年的两个时间点的初步数据显示，随着时间的推移，CMV DNA状态的变化与CMV特异性CD8 T细胞和IL-6水平的变化平行，而抗CMV IgG滴度保持不变。我们提出了两个目的：1)验证抗巨细胞病毒IgG血清学不能预测老年人单核细胞中巨细胞病毒DNA随时间的存在和变化的假设；2)验证单核细胞中巨细胞病毒DNA比抗巨细胞病毒IgG血清学更能预测以下疾病的假设：a)通过cmv特异性和干扰素（IFN)-g产生的CD8 T细胞和终末分化的T细胞亚群（CD28-， CD27-和CD45RA+）的扩增来测量T细胞免疫衰老，b） IL-6和neopterin水平升高。获得的数据将最终使我们能够建立慢性巨细胞病毒感染与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，这一数据将为进一步研究慢性巨细胞病毒感染导致老年人不良健康结局的基本免疫学和炎症机制开辟新的研究途径，这将通过包括R01在内的其他资助机制进行。主要的健康影响包括通过预防或减轻慢性巨细胞病毒感染及其对这一弱势群体的免疫和健康的不利影响，促进成功老龄化和维持功能。

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.