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（由申请方提供）：基孔肯雅病毒（CHIKV）是NIAID C类优先病原体，可导致人类失能性肌肉骨骼疾病，其特征为行走能力受损和外周关节剧烈疼痛，持续数周至数月。在2004-2007年涉及数百万患者的CHIKV爆发性流行期间，受感染的旅行者直接导致CHIKV在非流行国家的引入。基孔肯雅翻译为“弯曲关节的东西”，反映了大多数感染者所经历的令人衰弱的风湿症状。高达64%的患者在首次诊断后一年多报告持续的风湿性症状，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以以循环方式发生，表明疾病症状的复发是通过未知机制发生的。我们已经开发了一种CHIKV感染的小鼠模型，其中主要的病理结果，关节炎，肌炎和腱鞘炎，与大多数CHIKV感染的人所经历的临床体征一致。引人注目的是，我们发现组织病理学变化和CHIKV RNA在CHIKV接种的小鼠的关节组织中持续接种后至少三周，这表明病毒或病毒RNA的持续存在可能驱动慢性炎症。我们在接种后3周从小鼠关节组织中分离了CHIKV RNA，并表明它在转染到细胞中时具有传染性，这表明传染性CHIKV基因组持续存在于组织中。基于这些研究，我们假设CHIKV诱导的风湿性疾病的持续性与持续性CHIKV感染相关。为了检验这一假设，在目的1中，我们将定义CHIKV感染的持续时间和性质以及关节组织中的组织病理学变化。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在关节中的持续性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在关节组织中持续存在，但从非关节组织中有效清除。在目的2中，我们将使用一组在适应性免疫应答的组分中具有遗传定义的缺陷的小鼠来定义负责从非关节组织清除CHIKV的免疫学机制。此外，我们将确定感染后免疫抑制的程度与CHIKV复制和风湿性疾病体征的复苏相关。这些研究直接解决了该领域的一个突出问题，即持续的CHIKV诱导的风湿性疾病体征是否与持续感染相关。定义这种关联和调节CHIKV清除的免疫机制以及感染的部位和持续时间具有重要的治疗和公共卫生意义，包括告知用于治疗慢性CHIKV诱导的风湿性疾病症状的治疗策略以及关于在具有CHIKV活性的地区进行血液和组织捐献的政策。 公共卫生相关性：基孔肯雅病毒引起爆炸性流行病，并已蔓延到世界许多地区，使其成为一个主要的新兴疾病威胁。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，通常会变成慢性。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。