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

老年人慢性巨细胞病毒感染：诊断及其与慢性炎症的联系

• 批准号: 8429619
• 负责人: Sean Xiao Leng
• 金额: $ 24.3万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8429619
• 关键词: Address; Aging; American; Anemia; Antibodies; Biological Assay; Biology; Blood Cells; CD28 gene; CD8B1 gene; Chronic; Clinical; Clonal Expansion; Cohort Studies; Conflict (Psychology); Coronary Arteriosclerosis; Cytomegalovirus; Cytomegalovirus Infections; DNA; DNA Viruses; Data; Development; Diagnosis; Disease; Elderly; Exposure to; Fostering; Funding; Funding Mechanisms; Health; Heterogeneity; Immune; Immunity; Immunoglobulin G; Infection; Inflammation; Inflammatory; Interferons; Interleukin-6; Link; Literature; Measures; Neopterin; Nested PCR; Outcome; Peripheral Blood Mononuclear Cell; Persons; Pilot Projects; Population; Prevalence; Prevention; Publishing; Reporting; Research; Role; Serologic tests; Serum; Syndrome; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Time; United States National Institutes of Health; Viral Genome; Virus; Visit; Vulnerable Populations; Women' s Health; age related; base; disability; frailty; immune activation; immunosenescence; innovation; insight; longitudinal analysis; monocyte; mortality; peripheral blood; public health relevance; viral DNA

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.

描述（由申请人提供）：我们和其他人提供的大量证据表明，以 IL-6 升高为标志的慢性炎症状态会导致老年人出现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。研究报告了巨细胞病毒 (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、残疾和死亡率的关联。然而，文献中存在大量的冲突报告。这是因为抗 CMV IgG 血清学是一种粗略的测量方法，仅表明之前是否接触过病毒，并且不区分过去（已解决）或慢性（持续）感染。 CMV 生物学表明，虽然大多数人都接触过该病毒，但 CMV 可以在某些人体内持续存在，其病毒基因组 (DNA) 存在于外周血单核细胞中，这代表一种慢性感染。该应用旨在表征通过基于巢式 PCR 的检测检测到的单核细胞中的 CMV 病毒 DNA，并测试单核细胞中的 CMV DNA 比抗 CMV IgG 血清学更好地预测老年人 T 细胞免疫衰老和慢性炎症的假设。我们将在女性健康和衰老研究 II 中使用深入的纵向分析，这是一项由 NIA 资助的大型队列研究，其中使用了 12 年来 7 次访问时收集的外周血单核细胞 (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含有 CMV DNA，并且 CMV DNA（而非 IgG 滴度）与 CMV 特异性 CD8 T 细胞增加和 CMV 特异性 CD8 T 细胞增加相关。血清新蝶呤和 IL-6 水平。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，2) 检验单核细胞中 CMV DNA 是更好的预测的假设比抗 CMV IgG 血清学的预测因子： a) 通过 CMV 特异性和产生干扰素 (IFN)-g 的 CD8 T 细胞和终末分化 T 细胞亚群的扩增来测量 T 细胞免疫衰老（CD28-、CD27- 和 CD45RA+），b) IL-6 和新蝶呤水平升高。获得的数据最终将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基本免疫学和炎症机制开辟新的研究途径，慢性 CMV 感染通过这些机制导致老年人出现不良健康结果，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弱势群体免疫和健康的不利影响来促进成功老龄化和维持功能。