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）：披膜病毒科甲病毒属包括作为重要人类病原体的病毒。基孔肯雅病毒 (CHIKV) 是一种虫媒病毒，通过受感染的蚊媒叮咬在人类和非人类灵长类动物之间传播。 CHIKV 周期性地在非洲、亚洲和美洲热带地区的幼稚人群中引起爆炸性流行。自 2005 年初以来，CHIKV 流行已导致印度和印度洋岛屿留尼汪岛、毛里求斯、马达加斯加和塞舌尔超过 150 万例 CHIK 热病例。此外，从这些地区返回欧洲、加拿大和美国的旅行者被诊断出患有这种疾病，这增加了世界其他地区爆发疫情的可能性。尽管当前的流行病导致的死亡人数高于典型情况，但 CHIK 热很少致命。在成人中，这种感染类似于登革热，会导致急性发热性疾病，并伴有剧烈的肌肉和关节疼痛。在最初的疾病消失后，关节痛/关节炎的症状通常会持续数周或数月。然而，疾病的严重程度很大程度上取决于年龄：受感染的儿童很少出现关节炎，但通常会出现热性惊厥，并可能伴有神经系统后遗症和出血表现。尽管 CHIKV 会导致流行/大流行规模的严重人类疾病，但该病毒的发病机制在很大程度上仍不明确，没有获得许可的疫苗，并且人类感染的治疗仅限于支持性护理。 拟议研究的目的是了解病毒/宿主相互作用的机制，从而促进随后设计用于治疗急性疾病的疗法和用于保护的疫苗。开发一个基因定义的 CHIK 发病机制模型将有助于这些研究，其中包括两种天然 CHIKV 分离株的 cDNA 克隆：1983 年塞内加尔流行期间分离的 CHIKV-37997 株和 La Rhunion (CHIKV-LR)本次疫情早期在留尼汪岛分离出的菌株。我们建议通过探索病毒毒力和宿主反应来开发小鼠发病机制模型，准确再现人类 CHIKV 感染（出血性和关节炎性）的病因。该应用的具体目的是： 1) 表征乳鼠致命感染与成人自限性疾病中的发热反应和出血表现； 2) 表征老年小鼠非致命性疾病中 CHIKV 感染的关节炎表现； 3) 通过 CHIKV 的小鼠适应来改进小鼠发病机制模型。我们假设，致命性感染与非致命性感染的比较将确定宿主和病毒编码的疾病严重程度的决定因素。这些决定因素将为急性感染期间的治疗干预提供目标，无论是通过自然节肢动物传播还是生物战/生物恐怖袭击获得的。