Viral determinants of hantavirus pulmonary disease in the hamster

描述(申请人提供)：汉坦病毒肺综合征(HPS)是一种经常致命的人畜共患病，在新大陆流行。HPS的毒力似乎取决于汉坦病毒的遗传学。最近的研究结果表明，新大陆汉坦病毒在叙利亚金黄地鼠和人类中的毒力取决于病毒遗传学。因此，HPS的仓鼠模型为阐明毒力的病毒决定因素提供了一个独特的机会。这项拟议研究的长期目标是：1)阐明单独或共同决定新大陆汉坦病毒毒力的汉坦病毒基因组的遗传元件；2)扩大我们对HPS发病机制的了解；3)识别治疗HPS的抗病毒化合物；以及4)开发针对HPS的疫苗。第一个目标是开发一种基于质粒的遗传系统，使科学家能够将毒力的决定因素映射到汉坦病毒基因组的特定元素。基因系统的组成部分将用于未来的研究，以快速和经济地筛选出可以预防汉坦病毒感染或疾病的化合物。目的2是严格比较和对比6种不同但在基因上关系非常密切的新大陆汉坦病毒的致病性和毒力。目的#3是确定这6种病毒全基因组的遗传序列。基因序列数据库将与来自AIM#2的实验动物数据结合使用，以确定汉坦病毒基因组中可能与毒力相关的元件。目的#4是评估汉坦病毒基因组的大、中、小片段对HPS样疾病在仓鼠中的毒力的贡献。来自AIM#1的基于质粒的遗传系统将被用来产生来自马普拉病毒(MAPV)和汉坦病毒的重组病毒，MAPV在仓鼠中是高毒力的，而汉坦病毒在仓鼠中不是强毒，重要的是，它在基因上与MAPV密切相关。AIM#4的工作结果有望缩小未来研究的重点，以确定毒力的病毒决定因素。目的#5研究MAPV的小、中、大三个基因组片段在仓鼠HPS样病进化中的作用。将进行一系列时程研究，以评估1)基因组片段，2)病毒感染动力学和宿主对感染的反应，以及3)毒力之间的联系。与毒力一致的病毒基因组元件可能是基于序列的抗病毒治疗或疫苗开发的合适靶点。基于质粒的遗传系统可以用于未来的研究，以开发疫苗来预防感染或疾病，并(在临床疾病面前)减轻HPS的严重程度。

DESCRIPTION (provided by applicant): Hantavirus pulmonary syndrome (HPS) is a frequently fatal zoonosis that is endemic in the New World. The virulence of HPS appears to be dependent upon hantaviral genetics. The results of recent studies suggest that the virulence of the New World hantaviruses in Syrian golden hamsters, as in humans, is dependent upon viral genetics. Thus, the hamster model of HPS provides a unique opportunity to elucidate the viral determinants of virulence. The long-term objectives of the proposed research are to 1) elucidate the genetic elements of the hantaviral genome that individually or collectively determine the virulence of the New World hantaviruses, 2) extend our knowledge of the pathogenesis of HPS, 3) identify antiviral compounds for therapy of HPS, and 4) develop vaccines against HPS. Aim #1 is to develop a plasmid-based genetic system that will enable scientists to map the determinants of virulence to specific elements of the hantaviral genome. Components of the genetic system will be used in future studies to rapidly and economically screen for compounds that can prevent hantaviral infection or disease. Aim #2 is to rigorously compare and contrast the pathogenicity and virulence of 6 different but genetically very closely related New World hantaviruses. Aim #3 is to determine the genetic sequences of the complete genomes of these 6 viruses. The genetic sequence database will be used in combination with the experimental animal data from Aim #2 to identify elements of the hantaviral genome that may be causally associated with virulence. Aim #4 is to assess the contribution of the large, medium, and small segments of the hantaviral genome to the virulence of HPS-like disease in the hamster. The plasmid-based genetic system from Aim #1 will be used to generate reassortant viruses from Maporal virus (MAPV), which is highly virulent in hamsters, and a hantavirus that is not virulent in hamsters and, importantly, that is genetically closely related to MAPV. The results of the work in Aim #4 are expected to narrow the focus of future studies to identify the viral determinants of virulence. Aim #5 is to investigate the effect of the small, medium, and large genomic segments of MAPV on the evolution of HPS-like disease in hamsters. A series of time-course studies will be done to assess the association between 1) genomic segment, 2) kinetics of viral infection and host response to infection, and 3) virulence. Elements of the viral genome that align with virulence may be appropriate targets for sequence-based antiviral therapy or vaccine development. The plasmid-based genetic system could be used in future studies to develop vaccines to prevent infection or disease and to (in the face of clinical disease) mitigate the severity of HPS.