Mechanisms of Fatigue in a Chronic Viral Disease

描述(申请人提供)：许多人患有需要长期或终身医疗管理的疾病。这些疾病的病因可以是传染性的(如病毒性肝炎、人类免疫缺陷病毒、疱疹病毒)或非传染性的(如肾功能衰竭、自身免疫性疾病、癌症)，以及相关的治疗方法，通常与疲劳、非恢复性睡眠和白天过度嗜睡有关。此外，越来越多的人患有原因不明的慢性疲劳症。过度的嗜睡和疲劳，特别是在持续的时候，会降低受影响个人的生活质量，还会造成重大的经济损失，因为错误率增加，生产力降低，就业能力减弱。疲劳在这个社会中的重要性与日俱增，这促使人们有必要扩大对这种令人衰弱的症状的理解。小鼠感染小鼠的伽马疱疹病毒-68(MuGHV)与人类感染EB病毒(EBV)的许多免疫学和病理生理学特征相似。初步数据表明，受感染的小鼠会出现疲劳和睡眠障碍，这些症状会持续到活动性(溶血性)感染后，并会因应激而加剧。我们将使用这个模型通过完成以下特定目标来描述慢性感染后疲劳的特征和机制：1)量化和评估感染MuGHV的小鼠的睡眠和疲劳的发展；a)在感染的活动期和潜伏期，b)细菌和病毒产品二次免疫攻击后，以及c)删除干扰素-γ之后；2)量化和评估破坏性生活事件对潜在的MuGHV感染小鼠疲劳和病毒重新激活的影响a)对社会压力、睡眠缺失和运动的反应，以及b)删除干扰素-γ之后。在这两个目标中，测量特定大脑区域和外围器官中潜伏期和睡眠调节细胞因子导致的病毒重新激活的相关变化，以及脾和肺中病毒重新激活的相关变化。这些问题将作为小鼠遗传背景、小鼠性别以及白天和感染后时间的函数来解决。创建一个模型系统，以支持描述感染后疲劳的产生机制，为制定预防或减轻这一致残性疾病后果的干预措施奠定了重要基础。这样的长期结果将改善跨越多种疾病的目标人群的生活质量和经济福利。公共卫生意义：许多人患有各种慢性疾病，需要长期或终身的医疗管理。这些疾病的病因可以是传染性的(如病毒性肝炎、人类免疫缺陷病毒、疱疹病毒)，也可以是非传染性的(如肾功能衰竭、自身免疫性疾病、癌症)及其相关的治疗方法，通常与疲劳、非恢复性睡眠和白天过度嗜睡有关。越来越多的人还患有原因不明的慢性疲劳症。过度的嗜睡和疲劳，特别是在持续的时候，会降低受影响个人的生活质量，还会造成重大的经济损失，因为错误率增加，生产力降低，就业能力减弱。疲劳在这个社会中的重要性与日俱增，这促使人们有必要扩大对这种令人衰弱的症状的理解。查明产生慢性疲劳和日间过度嗜睡的机制，并为这些致残问题制定有效的干预措施，可以改善许多人的经济福利和生活质量。然而，由于许多原因，在人类身上进行适当和必要的研究是困难的。发展有效的动物模型将极大地促进这一领域的进展。我们建议研究小鼠的小鼠伽马疱疹病毒68(MuGHV)感染，作为人类感染后疲劳的模型条件。小鼠的MuGHV模仿了人类传染性单核细胞增多症的许多免疫学和病理生理学特征。创建一个有效的模型系统来研究这些病毒感染过程中疲劳的原因，将为发现和开发预防或减轻这种人类致残性疾病后果的治疗方法奠定基础。这样的长期结果将改善跨越多种疾病的目标人群的生活质量和经济福利。

DESCRIPTION (provided by applicant): Many people suffer from disorders that require long-term or life-long medical management. These diseases, whose etiologies can be infectious (e.g., viral hepatitis, human immunodeficiency virus, herpesviruses) or non-infectious (e.g., renal failure, autoimmune diseases, cancer), and the associated therapies, are often associated with fatigue, non-restorative sleep, and excessive daytime sleepiness. In addition, growing numbers of individuals suffer from debilitating chronic fatigue of undetermined etiology. Excessive sleepiness and fatigue, particularly when persistent, reduce the quality of life of affected individuals and also cause significant economic loss in terms of increased error rates, reduced productivity, and diminished employment capability. The growing importance of fatigue in this society has stimulated a need to expand understanding of this debilitating symptom. Murine gammaherpesvirus-68 (MuGHV) infection in mice mimics many of the immunologic and pathophysiological features of Epstein-Barr virus (EBV) infection in people. The preliminary data indicate that infected mice develop fatigue and sleep perturbations that persist beyond the period of active (lytic) infection and can be exacerbated by stress. We will use this model to delineate the characteristics and mechanisms of chronic post-infective fatigue by completing the following Specific Aims: 1) quantify and assess sleep and the development of fatigue in mice infected with MuGHV a) during active and latent phases of infection, b) after secondary immunologic challenge with bacterial and viral products, and c) after deletion of IFN-gamma; 2) quantify and assess the impact of disruptive life events on fatigue and viral reactivation in mice with latent MuGHV infections a) in response to social stress, sleep loss, and exercise, and b) after deletion of IFN-gamma. In both Aims, measure associated changes in viral reactivation from latency and sleep-modulatory cytokines in specific brain regions and peripheral organs, and in viral reactivation in spleen and lung. These questions will be addressed as a function of mouse genetic background, mouse gender, and diurnal and post-infection timing. Creating a model system to support the delineation of mechanisms that generate post-infective fatigue establishes an essential foundation for the development of interventions that will prevent or alleviate this disabling disease outcome. Such a long-term result would improve the quality of life and economic welfare of target populations that span many disease conditions. Public Health Significance: Many people suffer chronically from a wide variety of disorders that require long-term or life-long medical management. These diseases, whose causes can be infectious (e.g., viral hepatitis, human immunodeficiency virus, herpesviruses) or non-infectious (e.g., renal failure, autoimmune diseases, cancer), and their associated therapies, are often associated with fatigue, non-restorative sleep, and excessive daytime sleepiness. Growing numbers of individuals also suffer from debilitating chronic fatigue of unknown cause. Excessive sleepiness and fatigue, particularly when persistent, reduce the quality of life of affected individuals and also cause significant economic loss in terms of increased error rates, reduced productivity, and diminished employment capability. The growing importance of fatigue in this society has stimulated a need to expand understanding of this debilitating symptom. Identifying the mechanisms that generate chronic fatigue and excessive daytime sleepiness and developing effective interventions for these disabling problems could improve the economic welfare and quality of life of many individuals. Nevertheless, conducting the appropriate and necessary studies in humans is difficult for many reasons. Progress in this area would be greatly facilitated by the development of a valid animal model. We propose to study murine gammaherpesvirus-68 (MuGHV) infection in mice as a model condition for human post-infective fatigue. MuGHV in mice mimics many of the immunologic and pathophysiological features of infectious mononucleosis, or "mono," in people. Creating a valid model system for studying the causes of fatigue during these viral infections will establish a foundation for the discovery and development of treatments to prevent or alleviate this disabling disease outcome in people. Such a long-term result would improve the quality of life and economic welfare of target populations that span many disease conditions.