Persistent chikungunya virus infection and disease

持续的基孔肯雅病毒感染和疾病

• 批准号: 8268966
• 负责人: Thomas E Morrison
• 金额: $ 18.78万
• 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/8268966
• 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.

描述（由申请人提供）：Chikungunya病毒（CHIKV）是一种NIAID类别的病原体，导致人类中肌肉骨骼疾病丧失的能力，其特征是在外周血关节中行动和强烈疼痛的能力受损，持续数周到几个月。在2004 - 2007年爆炸性的CHIKV流行期间，涉及数百万名患者的流行病，被感染的旅行者直接导致了非流行国家的Chikv。 Chikungunya翻译成“弯曲关节的曲子”，并反映了大多数受感染者经历的令人衰弱的风湿性症状。初次诊断后一年多一年以上，多达64％的患者报告了持续性的风湿性症状，而3 - 5年后仍有12％的症状报告。有趣的是，与CHIKV感染相关的慢性关节症状可能以环状方式发生，这表明疾病症状的复活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，其中主要病理结局，关节炎，肌瘤和替索诺泳炎与大多数CHIKV感染的人所经历的临床体征一致。令人惊讶的是，我们发现在接种后至少三周，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的持续性可能驱动慢性炎症。我们在接种后3周将Chikv RNA从鼠关节组织中分离出来，并表明当转染细胞时，它具有感染性，表明感染性的Chikv基因组持续存在于组织中。基于这些研究，我们假设Chikv诱导的风湿病的持续性与持续的Chikv感染有关。为了检验这一假设，在AIM 1中，我们将定义关节组织中CHIKV感染和组织病理学变化的持续时间和性质。此外，我们将使用454个测序来定义持续感染的关节组织中存在的病毒基因型，以检验关节中Chikv持久性与选择独特的病毒变异的假设。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AIM 2中，我们将使用一组具有遗传定义缺陷的小鼠在自适应免疫反应的成分中，以定义负责从非关节组织CHIKV清除率的免疫机制。此外，我们将定义感染后免疫抑制的程度与Chikv复制和风湿病症状的复活有关。这些研究直接解决了持续性CHIKV诱发的风湿病迹象与持续感染有关的一个杰出问题。定义这种关联以及调节CHIKV清除率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影响，包括告知治疗Chikv活性区域的慢性CHIKV诱发的慢性CHIKV诱发的风湿性疾病症状以及有关血液和组织捐赠的政策。