Persistent chikungunya virus infection and disease

持续的基孔肯雅病毒感染和疾病

• 批准号: 8177987
• 负责人: Thomas E Morrison
• 金额: $ 22万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8177987
• 关键词: Address; Alphavirus; Anti-Inflammatory Agents; Anti-inflammatory; Area; Arthralgia; Arthritis; Blood Donations; Categories; Cell Line; Cells; Chikungunya virus; Chronic; Chronic Disease; Clinical; Coculture Techniques; Country; Culicidae; Diagnosis; Disease; Epidemic; Genome; Genotype; Human; Immune response; Immune system; Immunohistochemistry; Immunosuppression; Immunosuppressive Agents; In Situ Hybridization; Indian Ocean; Individual; Infection; Infectious Arthritis; Inflammation; Italy; Joints; Lead; Modeling; Mus; Musculoskeletal Diseases; Musculoskeletal System; Mutation; Myositis; National Institute of Allergy and Infectious Disease; Nature; Outcome; Pain; Pathology; Patients; Peripheral; Persons; Pharmaceutical Preparations; Policies; Process; Public Health; RNA; Regulation; Relative (related person); Reporting; Resolution; Reverse Transcriptase Polymerase Chain Reaction; Rheumatism; Role; Signs and Symptoms; Site; Symptoms; Tenosynovitis; Testing; Therapeutic; Tissue Donations; Tissues; Transfection; Translating; United States; Variant; Vero Cells; Viral; Viral Antigens; Viral Genome; Virus; Virus Diseases; Virus Replication; Wild Type Mouse; adaptive immunity; arthropathies; base; chikungunya; experience; intense pain; mouse model; pathogen; research study; treatment strategy; vector mosquito; viral RNA

DESCRIPTION (provided by applicant): Chikungunya virus (CHIKV), an NIAID category C priority pathogen, causes incapacitating musculoskeletal disease in humans characterized by an impaired ability to ambulate and intense pain in the peripheral joints that lasts for weeks to months. During the explosive 2004-2007 epidemic of CHIKV that involved millions of patients, infected travelers led directly to the introduction of CHIKV in nonendemic countries. Chikungunya translates as "that which bends up the joints," and reflects the debilitating rheumatic symptoms that are experienced by most infected individuals. Up to 64% of patients reported persistent rheumatic symptoms more than one year after initial diagnosis, and 12% still reported symptoms 3-5 years later. Interestingly, chronic joint symptoms associated with CHIKV infection can occur in a cyclic manner, suggesting resurgence of disease symptoms occurs by unknown mechanisms. We have developed a mouse model of CHIKV infection in which the major pathological outcomes, arthritis, myositis, and tenosynovitis, are consistent with the clinical signs experienced by the majority of CHIKV-infected humans. Strikingly, we found that both histopathological changes and CHIKV RNA persisted in joint tissues of CHIKV-inoculated mice for at least three weeks post- inoculation, suggesting that the persistence of virus or viral RNA may drive chronic inflammation. We isolated CHIKV RNA from murine joint tissues at 3 weeks post-inoculation and showed that it was infectious when transfected into cells, indicating that infectious CHIKV genomes persisted in tissues. Based on these studies, we hypothesize that persistence of CHIKV-induced rheumatic disease is associated with persistent CHIKV infection. To test this hypothesis, in Aim 1 we will define the duration and the nature of CHIKV infection and histopathological changes in joint tissues. In addition, we will use 454 sequencing to define the viral genotypes present in persistently infected joint tissue to test the hypothesis that CHIKV persistence in joints is associated with the selection of unique viral variants. Our preliminary studies indicate that CHIKV persists in joint tissue yet is efficiently cleared from non-joint tissues. In Aim 2, we will use a panel of mice with genetically-defined deficiencies in components of the adaptive immune response to define the immunological mechanisms responsible for CHIKV clearance from non-joint tissues. In addition, we will define the extent to which immunosuppression after infection is established is associated with a resurgence of CHIKV replication and rheumatic disease signs. These studies directly address an outstanding question in the field of whether persistent CHIKV-induced rheumatic disease signs are associated with persistent infection. Defining this association and the immunological mechanisms that regulate CHIKV clearance and the sites and duration of infection has important treatment and public health implications, including informing therapeutic strategies for the treatment of chronic CHIKV-induced rheumatic disease symptoms and policies regarding blood and tissue donation in regions with CHIKV activity. PUBLIC HEALTH RELEVANCE: Chikungunya virus causes explosive epidemics and has spread to many regions of the world, making it a major emerging disease threat. Infection of humans with chikungunya virus leads to debilitating pain and inflammation of the musculoskeletal system that often becomes chronic. The studies proposed in this application will help understand how chikungunya virus infection causes chronic musculoskeletal disease and the immunological mechanisms that regulate these processes.

描述（由申请人提供）：基孔肯雅病毒 (CHIKV) 是一种 NIAID C 类优先病原体，会导致人类丧失能力的肌肉骨骼疾病，其特征是行走能力受损和周围关节剧烈疼痛，持续数周至数月。 2004-2007 年 CHIKV 爆发性流行期间，涉及数百万患者，受感染的旅行者直接导致 CHIKV 在非流行国家传入。基孔肯雅热翻译为“使关节弯曲的疾病”，反映了大多数感染者所经历的使人虚弱的风湿症状。高达 64% 的患者在初次诊断后一年多报告持续存在风湿症状，12% 的患者在 3-5 年后仍报告症状。有趣的是，与 CHIKV 感染相关的慢性关节症状可能以循环方式发生，表明疾病症状的复发是通过未知机制发生的。我们开发了 CHIKV 感染的小鼠模型，其中主要病理结果，关节炎、肌炎和腱鞘炎，与大多数 CHIKV 感染人类经历的临床症状一致。引人注目的是，我们发现在接种 CHIKV 的小鼠的关节组织中，组织病理学变化和 CHIKV RNA 持续存在至少三周，这表明病毒或病毒 RNA 的持续存在可能会导致慢性炎症。我们在接种后 3 周从小鼠关节组织中分离出 CHIKV RNA，并显示其在转染到细胞中时具有感染性，这表明感染性 CHIKV 基因组在组织中持续存在。基于这些研究，我们假设 CHIKV 诱导的风湿病的持续存在与持续的 CHIKV 感染有关。为了检验这一假设，在目标 1 中，我们将定义 CHIKV 感染的持续时间和性质以及关节组织的组织病理学变化。此外，我们将使用 454 测序来定义持续感染的关节组织中存在的病毒基因型，以检验 CHIKV 在关节中的持续存在与独特病毒变体的选择相关的假设。我们的初步研究表明，CHIKV 持续存在于关节组织中，但可以从非关节组织中有效清除。在目标 2 中，我们将使用一组在适应性免疫反应成分中具有遗传定义缺陷的小鼠来定义负责从非关节组织清除 CHIKV 的免疫机制。此外，我们将确定感染后免疫抑制与 CHIKV 复制和风湿病症状重新出现的相关程度。这些研究直接解决了 CHIKV 引起的持续性风湿性疾病症状是否与持续性感染相关这一领域的一个突出问题。定义这种关联以及调节 CHIKV 清除以及感染部位和持续时间的免疫学机制具有重要的治疗和公共卫生意义，包括为治疗慢性 CHIKV 诱发的风湿病症状的治疗策略以及在 CHIKV 活动地区有关血液和组织捐献的政策提供信息。 公共卫生相关性：基孔肯雅病毒引起爆炸性流行病，并已传播到世界许多地区，使其成为新出现的主要疾病威胁。人类感染基孔肯雅病毒会导致肌肉骨骼系统的衰弱性疼痛和炎症，并且往往会变成慢性。本申请中提出的研究将有助于了解基孔肯雅病毒感染如何导致慢性肌肉骨骼疾病以及调节这些过程的免疫机制。