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）：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了许多与年龄相关的疾病，脆弱，残疾和老年人死亡率。尽管如此，导致这种慢性炎症状态的原因和基本机制仍有待定义。研究报道了CMV阳性老年人中巨细胞病毒（CMV）特异性T细胞的克隆扩张，以及CMV血清阳性或绝对滴度的关联，或具有脆弱性，残疾，AD死亡率的绝对滴度。但是，文献中存在充分的冲突报告。这是因为抗CMV IgG血清学是一种粗略的措施，仅表示事先暴露于病毒，并且没有区分过去（解决）或慢性（持续性）感染。 CMV生物学表明，尽管大多数人暴露于病毒，但CMV可以在某些病毒基因组（DNA）中持续存在，其中包含在外周血单核细胞中，代表慢性感染。该应用旨在表征通过基于PCR的测定法检测到的单核细胞中的CMV病毒DNA，并检验了单核细胞中的CMV DNA预测与抗CMV IGG血清学更好的老年人中T细胞免疫延迟和老年人的慢性炎症。我们将在妇女健康和衰老研究II中使用深入的纵向分析，这是一项大型NIA资助的队列研究，其中包含养生的外周血单核细胞（PBMC），并在12年期间收集了7次访问时的血清。我们已发表的试点研究支持了我们的假设，即单核细胞中只有约50％-60％的CMV剧本阳性老年人具有CMV DNA，并且CMV DNA（而不是IgG滴度）与CMV特异性CD8 T细胞和升高的CD8 T细胞和升高的血清NEOPTERIN和IL-6水平有关。在两个时间点相隔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水平并行，而抗CMV IgG滴度保持不变。 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） - 产生G的CD8 T细胞和末端分化的T细胞亚集（CD28-，CD27-和CD45RA+），以及b）升高的IL-6和Neopterin水平。获得的数据最终将使我们能够在慢性CMV感染与T细胞免疫衰老和慢性炎症之间建立联系。如果我们的假设得到证实，则该数据将开辟新的研究途径，以进一步研究基本的免疫学和炎症机制，通过这些机制，慢性CMV感染有助于老年人不良健康结果的发展，这将通过包括R01在内的其他资金机制进行。主要的健康影响包括通过预防或减轻慢性CMV感染来促进成功的衰老和维持功能，及其对这种脆弱人群的免疫和健康的不利影响。