Mechanisms of Fatigue in a Chronic Viral Disease

慢性病毒性疾病中的疲劳机制

• 批准号: 7846539
• 负责人: Linda A Toth
• 金额: $ 1.98万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-05 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7846539
• 关键词: A Mouse; Acute; Address; Affect; Animal Model; Area; Autoimmune Diseases; Behavioral; Biological Assay; Biological Models; Brain region; Characteristics; Chronic; Chronic Disease; Data; Development; Disease; Disease Outcome; Economics; Employment; Epstein-Barr Virus Infections; Etiology; Event; Excessive Daytime Sleepiness; Exercise; Fatigue; Foundations; Gender; Genetic; HIV; Herpesviridae; Human; Human Herpesvirus 4; Immune; Immunologics; Impairment; Individual; Infection; Infectious Mononucleosis; Inflammatory; Interferon Type II; Intervention; Kidney Failure; Life; Link; Lung; Lytic Phase; Malignant Neoplasms; Measures; Medical; Modeling; Mono-S; Mus; Organ; Pathogenesis; Peripheral; Phase; Productivity; Public Health; Quality of life; Reagent; Research; Sleep; Sleep Disorders; Social Welfare; Societies; Spleen; Stress; Symptoms; System; Target Populations; Time; Treatment-Related Cancer; Viral; Viral hepatitis; Virus Diseases; Work; cost; cytokine; disabling disease; effective intervention; gammaherpesvirus; genetic variant; improved; latent infection; mouse model; prevent; reactivation from latency; response; social stress; therapy development

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.

描述（由申请人提供）：许多人患有需要长期或终身医疗管理的疾病。这些疾病的病因可能是传染性的（例如，病毒性肝炎，人免疫缺陷病毒，疱疹病毒）或非感染性（例如，肾衰竭、自身免疫性疾病、癌症）以及相关的治疗通常与疲劳、非恢复性睡眠和过度的日间嗜睡有关。此外，越来越多的个体患有病因不明的使人衰弱的慢性疲劳。过度的困倦和疲劳，特别是持续的困倦和疲劳，会降低受影响个体的生活质量，并在错误率增加、生产力降低和就业能力下降方面造成重大的经济损失。疲劳在这个社会中的重要性日益增加，刺激了对这种使人衰弱的症状的理解。小鼠中的小鼠γ疱疹病毒-68（MuGHV）感染模拟人中EB病毒（EBV）感染的许多免疫学和病理生理学特征。初步数据表明，受感染的小鼠出现疲劳和睡眠紊乱，持续超过活动（裂解）感染期，并可因压力而加剧。我们将使用该模型通过完成以下特定目的来描绘慢性感染后疲劳的特征和机制：1）量化和评估MuGHV感染小鼠的睡眠和疲劳的发展a）在感染的活动期和潜伏期，B）在用细菌和病毒产物进行二次免疫攻击后，和c）在IFN-γ缺失后; 2）量化和评估破坏性生活事件对具有潜伏性MuGHV感染的小鼠的疲劳和病毒再活化的影响，a）响应于社会压力、睡眠丧失和运动，和B）在IFN-γ缺失后。在这两个目的中，测量特定脑区和外周器官中潜伏期和睡眠调节细胞因子引起的病毒再活化以及脾和肺中病毒再活化的相关变化。这些问题将作为小鼠遗传背景，小鼠性别，昼夜和感染后时间的函数来解决。创建一个模型系统，以支持描绘的机制，产生感染后疲劳建立了一个必要的基础，干预措施的发展，将防止或减轻这种致残性疾病的结果。这种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：许多人长期患有各种各样的疾病，需要长期或终身的医疗管理。这些疾病，其原因可能是传染性的（例如，病毒性肝炎，人免疫缺陷病毒，疱疹病毒）或非感染性（例如，肾衰竭、自身免疫性疾病、癌症）及其相关疗法通常与疲劳、非恢复性睡眠和过度的日间嗜睡有关。越来越多的人还患有不明原因的慢性疲劳。过度的困倦和疲劳，特别是持续的困倦和疲劳，会降低受影响个体的生活质量，并在错误率增加、生产力降低和就业能力下降方面造成重大的经济损失。疲劳在这个社会中的重要性日益增加，刺激了对这种使人衰弱的症状的理解。确定产生慢性疲劳和白天过度嗜睡的机制，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。尽管如此，由于多种原因，在人体中进行适当且必要的研究很困难。有效动物模型的开发将极大地促进这一领域的进展。我们建议研究小鼠γ疱疹病毒-68（MuGHV）感染小鼠作为人类感染后疲劳的模型条件。小鼠中的MuGHV模拟了人中传染性单核细胞增多症或“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期间疲劳的原因，将为发现和开发预防或减轻这种致残性疾病的治疗方法奠定基础。这种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。