Stress, Cellular Aging and Susceptibility to Infectious Disease

描述（由申请人提供）：该申请涉及广泛的挑战领域：（03）生物标志物的发现和验证以及特定的挑战主题：03- at -101*压力的精神神经免疫学生物标志物。鉴定生物标志物以评估社会和生物压力对免疫功能的影响。淋巴细胞（特别是CD8细胞）的细胞衰老率，如端粒长度的减少所表明的，可能是免疫能力的重要新标志，反过来，宿主对传染性病原体的抵抗力。端粒长度的丧失对于理解心理应激在感染性疾病中的作用可能特别重要。压力与上呼吸道病毒性疾病的易感性有关。此外，心理压力的增加与淋巴细胞端粒长度的缩短有关。这一证据表明，应激可能通过其对淋巴细胞衰老的影响而影响疾病易感性。此外，心理压力也与更高的氧化应激和更低的端粒酶活性有关。这两者都有助于端粒的缩短，这表明心理压力可能通过对这些端粒调节器的影响而缩短端粒。我们有一个独特的机会，通过在正在进行的病毒挑战研究中增加氧化应激、端粒酶活性和端粒长度基线的评估，来解决健康成人受试者的这些假设。父母研究中的基线测量包括一系列压力测量：通过问卷对压力进行心理和社会测量，评估三天内基本的皮质醇昼夜节律，以及在实验室对实验压力源的自主神经和皮质醇反应。在完成所有基线措施后，受试者暴露于经过安全测试的鼻病毒，并在隔离中监测感染和疾病的发展。局部（鼻腔分泌）释放促炎和抗炎细胞因子也评估病毒暴露后。大约40%的受试者在应对病毒挑战时出现临床疾病。在该研究的扩展中，我们建议评估端粒长度是否预测对感染和疾病表达的易感性，以及它是否构成胁迫影响对传染病抗性的中介途径。我们还可以确定端粒长度是否介导心理应激对局部产生的促炎性和抗炎性细胞因子的已知影响，这些细胞因子在疾病表达中起作用。最后，我们可以测试端粒酶活性和氧化应激是否构成心理、社会和生物应激标志物可能影响端粒长度的途径。这项工作对理解压力在衰老过程中的作用具有重要意义，特别是对减少老年人和那些经历长期压力的人（如长期失业者、照顾者和贫困人口）的疾病具有重要意义。

DESCRIPTION (provided by applicant): This application addressed Broad Challenge Area: (03) Biomarker Discovery and Validation and specific challenge topic: 03-AT-101* Psychoneuroimmunology biomarkers of stress. Identification of biomarkers to assess the impact of stress, both social and biological, on immune function. The rate of cell senescence in lymphocytes (particularly in CD8 cells), as indicated by decreases in telomere length, may be an important new marker of immunocompetence and, in turn, host resistance to infectious agents. Loss of telomere length may be especially important in understanding the role of psychological stress in infectious illness. Stress is associated with greater susceptibility to upper respiratory viral illnesses. In addition, increases in psychological stress are associated with shorter telomere length in lymphocytes. This evidence suggests that stress may influence disease susceptibility via its effects on lymphocyte cell senescence. Moreover, psychological stress has also been associated with greater oxidative stress and less telomerase activity. Both of these contribute to shortening of telomeres, suggesting that psychological stress may shorten telomeres via its effects on these telomere regulators. We have a unique opportunity to address these hypotheses in healthy adult human subjects by adding assessments of oxidative stress, telomerase activity and telomere length at baseline to an ongoing viral- challenge study. Baseline measures in the parent study include a range of stress measures: psychological and social measures of stress by questionnaire, assessments of basal diurnal cortisol rhythms over three days and of autonomic and cortisol response to an experimental stressor in the laboratory. After completing all baseline measures, subjects are exposed to a safety tested rhinovirus and monitored in quarantine for the development of infection and illness. Local (nasal secretory) release of pro- and anti- inflammatory cytokines are also assessed after viral exposure. Approximately 40% of the subjects develop a clinical illness in response to the viral challenge. In this extension of that study, we propose to evaluate whether telomere length predicts susceptibility to infection and disease expression and whether it constitutes a mediating pathway through which stress influences resistance to infectious disease. We can also determine whether or not telomere length mediates the known effects of psychological stress on the locally produced pro- and anti-inflammatory cytokines that play a role in illness expression. Finally, we can test whether or not telomerase activity and oxidative stress constitute pathways through which psychological, social and biological markers of stress might influence telomere length. This work has implications for understanding the role of stress in the aging process and particularly important implications for reducing disease in the elderly and those experiencing long-term stress (e.g. the chronically unemployed, caregivers, and those suffering from poverty). PUBLIC HEALTH RELEVANCE: A major focus of the project is to determine whether immune cell senescence (as assessed by telomere length) plays an important role in our ability to fight off infection. Because life stress has been found to be associated with greater senescence, we are also testing whether stress-associated increases in senescence can account for why life stress increases our risk for infectious diseases. An in-depth understanding of the role how stress influences our health can help lead to effective interventions to protect people at risk.