Viral determinants of hantavirus pulmonary disease in the hamster

仓鼠汉坦病毒肺病的病毒决定因素

基本信息

批准号：
7232754
负责人：
CHARLES F FULHORST
金额：
$ 33.62万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-06-01 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7232754
关键词：
2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole Affect Andes Virus Antibody Formation Antiviral Agents Antiviral Therapy Base Sequence Bunyamwera virus Bunyaviridae Categories Cells Cessation of life Clinical Complementary DNA Condition Cultured Cells Data Development Disease Dose Elements Evolution Face Facility Construction Funding Category Family Family member Fever Future Gene Mutation Genes Genetic Genetic Sequence Databases Genome Genomic Segment Genomics Genotype Hamsters Hantavirus Hantavirus Pulmonary Syndrome Human Immune response Infection Infection prevention Integration Host Factors Investigation Kinetics Knowledge La Crosse virus Laboratories Libraries Lung Lung diseases Lymphokines Maps Mesocricetus auratus Modeling Molecular Weight Muridae Mus Mutation National Institute of Allergy and Infectious Disease Orthobunyavirus Oryzomys Outcome Pathogenesis Pathogenicity Plasmids Point Mutation Prophylactic treatment RNA RNA-Directed RNA Polymerase Range Rattus Reassortant Viruses Research Research Personnel Research Proposals Rift Valley fever virus Rodent Scientist Series Severities Spleen System Testing Therapeutic Time Transgenic Organisms Vaccine Therapy Vaccines Viral Viral Genome Virulence Virulent Virus Virus Diseases Work Zoonoses animal data base cytokine genetic element in vivo member neutralizing antibody nonhuman primate pathogen prevent programs prophylactic research study response size vaccine development virus genetics

项目摘要

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.

描述（由申请人提供）：汉塔病毒肺综合征（HPS）是一种致命的人畜共患病，在新世界是特有的。 HPS的毒力似乎取决于汉坦病毒遗传学。最近的研究结果表明，与人类一样，叙利亚金仓鼠在叙利亚金仓鼠中的毒力取决于病毒遗传学。因此，HPS的仓鼠模型提供了一个独特的机会来阐明毒力的病毒决定因素。拟议研究的长期目标是1）阐明汉坦病毒基因组的遗传因素，这些基因组的遗传因素单独或集体确定新世界汉坦病毒的毒力，2）扩展我们对HPS的发病机理的了解，3）识别用于HPS治疗的抗生素化合物，以及4）发展疫苗抗HPS。目的1是开发基于质粒的遗传系统，该系统将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。遗传系统的组成部分将在未来的研究中使用，以快速和经济地筛选可以预防汉坦病毒感染或疾病的化合物。目标＃2是严格比较和对比6种不同但遗传密切相关的新世界汉坦病毒的致病性和毒力。目的＃3是确定这6种病毒的完整基因组的遗传序列。遗传序列数据库将与AIM＃2的实验动物数据结合使用，以识别可能与毒力有因果关系的汉坦病毒基因组的元素。目标＃4是评估汉坦病毒基因组的大，中和小部分对仓鼠中HPS样疾病的毒力的贡献。来自AIM＃1的基于质粒的遗传系统将用于从Maporal病毒（MAPV）中产生重新分类的病毒，该病毒在仓鼠中具有高度毒性，而在仓鼠中没有毒性的汉坦病毒，并且与MAPV遗传上密切相关。 AIM＃4中工作的结果预计将缩小未来研究的重点，以识别毒力的病毒决定因素。目标＃5是研究MAPV的小，中，大基因组段对仓鼠中HPS样疾病进化的影响。将进行一系列时间课程研究，以评估1）基因组段，2）病毒感染和宿主对感染的动力学的关联，以及3）毒力。与毒力保持一致的病毒基因组元素可能是基于序列的抗病毒治疗或疫苗发育的适当靶标。基于质粒的遗传系统可以在未来的研究中使用，以开发疫苗以防止感染或疾病，并（面对临床疾病）缓解HPS的严重程度。