Determining Molecular Mechanisms of Chikungunya Virulence and Attenuation

确定基孔肯雅热毒力和减毒的分子机制

• 批准号: 7996732
• 负责人: KATHERINE D RYMAN
• 金额: $ 23.94万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-22 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7996732
• 关键词: Molecular; Virulence; attenuation; chikungunya

DESCRIPTION (provided by applicant): The Alphavirus genus, family Togaviridae, includes viruses that are significant human pathogens. Chikungunya virus (CHIKV) is an arbovirus, transmitted between human and non-human primates by the bite of an infected mosquito vector. CHIKV periodically causes explosive epidemics in naive human populations in the African, Asian and American tropics. Since early 2005, a CHIKV epidemic has been responsible for over 1.5 million cases of CHIK fever in India and the Indian Ocean islands of Riunion, Mauritius, Madagascar and Seychelles. Furthermore, travelers returning to Europe, Canada and the United States from these areas have been diagnosed with the disease raising the possibility for outbreaks in other parts of the world. CHIK fever is rarely fatal, although the current epidemic is causing a higher than typical death toll. In adults, the infection resembles dengue fever, with acute febrile illness associated with excruciating muscle and joint pain. The symptoms of arthralgia/arthritis frequently persist for weeks or months later the initial illness has disappeared. However, the severity of disease is strongly age-dependent: infected children rarely develop arthritis, but commonly suffer febrile convulsions with possible associated neurologic sequelae and hemorrhagic manifestations. Although CHIKV causes severe human disease on an epidemic/pandemic scale, the pathogenesis of the virus remains largely uncharacterized, no licensed vaccine is available and the treatment of human infections is limited to supportive care. The objective of the proposed research is to provide an understanding of the mechanisms of virus/host interaction and thereby facilitate the subsequent design of therapeutics for the treatment of acute disease and vaccines for protection. These studies will be facilitated by the development of a genetically-defined pathogenesis model for CHIK, including a cDNA clone of two natural CHIKV isolates: the CHIKV-37997 strain isolated during an epidemic in Senegal, 1983 and the La Rhunion (CHIKV-LR) strain isolated on Riunion Island early in the current epidemic. We propose to develop murine pathogenesis models that accurately reproduce the etiologies of human CHIKV infection, both hemorrhagic and arthritogenic, by exploring virus virulence and host response. The specific aims of the application are: 1) To characterize the febrile response and hemorrhagic manifestations in fatal infection of suckling mice versus self-limiting disease in adults; 2) To characterize arthritogenic manifestations of CHIKV infection in non-fatal disease of older mice; and 3) To improve murine pathogenesis models by mouse-adaptation of CHIKV. We hypothesize that comparison of fatal to non-fatal infections will identify host- and virus-encoded determinants of disease severity. These determinants will provide targets for therapeutic intervention during acute infection, whether acquired from natural arthropod transmission or a biowarfare/bioterrorism attack.

描述（由申请人提供）：α病毒属，togaviridae家族，包括具有重要人类病原体的病毒。 Chikungunya病毒（Chikv）是一种arbovirus，通过被感染的蚊子载体的咬伤在人和非人类灵长类动物之间传播。 CHIKV会定期在非洲，亚洲和美国热带地区幼稚的人群中引起爆炸性的流行病。自2005年初以来，CHIKV流行病一直造成150万例CHIK Fever在印度和印度洋岛，毛里求斯，毛里求斯，马达加斯加和塞舌尔。此外，从这些地区返回欧洲，加拿大和美国的旅行者已被诊断出患有这种疾病，这增加了世界其他地区爆发的可能性。 CHIK热很少致命，尽管目前的流行病导致高于典型的死亡人数高。在成年人中，感染类似于登革热，与肌肉和关节疼痛相关的急性发热疾病。关节痛/关节炎的症状经常持续数周或几个月后，最初的疾病消失了。然而，疾病的严重程度密切依赖于年龄：感染儿童很少患有关节炎，但通常会出现发热性抽搐，并可能相关的神经系统后遗症和出血性表现。尽管CHIKV在流行病/大流行量表上引起严重的人类疾病，但该病毒的发病机理在很大程度上没有表征，没有持牌疫苗可用，并且人类感染的治疗仅限于支持性护理。 拟议的研究的目的是提供对病毒/宿主相互作用机制的理解，从而促进随后设计治疗急性疾病和保护疫苗的治疗方法。这些研究将通过开发CHIK的遗传定义的发病机制模型来促进，包括两个天然CHIKV分离株的cDNA克隆：Chikv-37997菌株在塞内加尔的流行病中分离的Chikv-37997菌株，1983年和La Rhunion（Chikv-LR）在Riunion Islard at riunion Islard hard at Iner当前的流行病中分离出来。我们建议通过探索病毒性毒力和宿主反应来准确地重现人类Chikv感染的病因，包括出血和关节化。该应用的具体目的是：1）表征哺乳小鼠致命感染的高热反应和出血性表现与成年人的自限性疾病； 2）表征奇克V感染在老鼠非致命疾病中的关节创造性表现； 3）通过小鼠适应chikv来改善鼠发病机理模型。我们假设将致命与非致命感染的比较将确定疾病严重程度的宿主和病毒编码的决定因素。这些决定因素将在急性感染期间提供治疗干预的靶标，无论是从天然节肢动物传播还是生物质量/生物恐怖主义攻击中获得的目标。