Determining Molecular Mechanisms of Chikungunya Virulence and Attenuation

描述（由申请方提供）：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，通过受感染的蚊子媒介的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、亚洲和美洲热带的未感染人群中引起爆发性流行。自2005年初以来，CHIKV流行病已导致印度和印度洋岛屿留尼汪、毛里求斯、马达加斯加和塞舌尔的150多万例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这种疾病的可能性。CHIK热很少致命，尽管目前的流行病造成的死亡人数高于典型的死亡人数。在成人中，感染类似于登革热，急性发热性疾病与痛苦的肌肉和关节疼痛有关。关节痛/关节炎的症状通常持续数周或数月，最初的疾病消失。然而，疾病的严重程度与年龄密切相关：受感染的儿童很少发生关节炎，但通常会出现热性惊厥，可能伴有神经系统后遗症和出血表现。尽管CHIKV在流行/大流行规模上引起严重的人类疾病，但病毒的发病机制在很大程度上仍未表征，没有许可的疫苗可用，并且人类感染的治疗仅限于支持性护理。 拟议研究的目的是提供对病毒/宿主相互作用机制的理解，从而促进随后设计用于治疗急性疾病的治疗方法和用于保护的疫苗。这些研究将通过开发CHIK的遗传学定义的发病机制模型来促进，包括两种天然CHIKV分离株的cDNA克隆：1983年在塞内加尔流行期间分离的CHIKV-37997株和在当前流行早期在Riunion岛上分离的La Rhunion（CHIKV-LR）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，其准确地再现人类CHIKV感染的病因，包括出血性和致关节炎性。本申请的具体目的是：1）表征乳小鼠致死性感染相对于成人自限性疾病的发热反应和出血表现; 2）表征老年小鼠非致死性疾病中CHIKV感染的致关节炎表现;和3）通过CHIKV的小鼠适应来改善鼠发病机制模型。我们假设，致命性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，无论是从自然节肢动物传播还是生物战/生物恐怖主义袭击中获得。

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.