Mechanism of Hepatitis E Virus Replication and Pathogenesis

戊型肝炎病毒复制和发病机制

• 批准号: 7575762
• 负责人: XIANG-JIN MENG
• 金额: $ 39.1万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7575762
• 关键词: Affect; Alleles; Amino Acid Sequence; Amino Acids; Animal Hepatitis; Animal Model; Animals; Appearance; Attenuated; Attenuated Live Virus Vaccine; Award; Baculovirus Expression System; Baculoviruses; Biological Models; Biological Process; Biology; Birds; Cambodia; Capsid; Capsid Proteins; Cell Culture Techniques; Cell Line; Cells; Chickens; Chimera organism; Communities; Complementarity Determining Regions; Complementary DNA; Consult; Data; Developed Countries; Developing Countries; Development; Disease; Disease model; Epidemic; Evolution; Family suidae; Funding; Future; Genes; Genome; Genomics; Genotype; Grant; Hepatitis; Hepatitis E; Hepatitis E virus; Human; Human Cloning; In Vitro; Infection; Knowledge; Length; Macaca mulatta; Maps; Modeling; Modification; Molecular; Molecular Biology; Mutation; National Institute of Allergy and Infectious Disease; Pathogenesis; Pathogenicity; Phenotype; Predisposition; Pregnant Women; Preventive; Primates; Process; Proteins; Public Health; Publishing; RNA Viruses; RNA chemical synthesis; Research; Role; Silent Mutation; Small RNA; Structural Protein; Study Section; System; Techniques; Testing; Time; Tropism; United States; United States National Institutes of Health; Vaccines; Variant; Vertebral column; Viral; Viral Pathogenesis; Viremia; Virus; Virus Diseases; Virus Replication; Virus Shedding; Work; attenuation; base; in vivo; mortality; mutant; nonhuman primate; pathogen; programs; public health relevance; research study; three dimensional structure; vaccine development; virus genetics; virus pathogenesis

DESCRIPTION (provided by applicant): Hepatitis E virus (HEV), the causative agent of human hepatitis E, is an important public health problem in developing countries, and is also endemic in the United States and other industrialized countries. The mortality rate associated with HEV infection is up to 28% in pregnant women. Due to the lack of a cell culture and a practical animal model system, the mechanisms of HEV replication and pathogenesis are poorly understood and a vaccine against hepatitis E is still not available. Our recent discoveries of swine and avian hepatitis E viruses from pigs and chickens and the demonstrated abilities of cross-species infections by the animal HEV strains have opened up new avenues for HEV research. Hepatitis E now is a recognized zoonotic disease, and pigs (and maybe other animal species) are known reservoirs. This proposal is based on our recent discoveries of swine and avian HEVs, establishment of pig and chicken models for HEV, construction of infectious cDNA clones of human, swine and avian HEVs, and identification of cell lines supporting HEV replication resulting from two prior NIH awards on HEV (AI01653, AI46505) which have now expired. The PI decided not to submit competing renewals so that he can combine the directions of the expired awards and expand the scope of his HEV research by submitting a single new proposal. The long-term objectives are to understand the mechanisms of HEV replication, pathogenesis and cross-species infection by using pigs, chickens and non-human primates as models, and by using avian-swine, avian-human and swine-human HEV chimeras to identify genomic regions that are functionally important for these processes. In this proposal, we aim to: (1). Determining the role(s) of the hypervariable region (HVR) in HEV replication and pathogenesis; (2). Understand the molecular basis of HEV cross-species infection and host susceptibility; and (3). Fine-map the amino acid residue(s) on HEV capsid protein that are important for HEV attenuation. This will be accomplished by using standard techniques including cell cultures, molecular biology, and animal studies. The proposed studies will significantly advance our understanding of the mechanisms of HEV replication, pathogenesis and cross- species infection, and will provide useful information for future vaccine development. PUBLIC HEALTH RELEVANCE: The lack of knowledge on HEV basic biology and pathogenesis has greatly hindered the development of a vaccine against HEV. The information gained from this project will help understand the mechanisms of HEV replication and pathogenesis, and help devise effective preventive and control strategies (such as a live-attenuated vaccine) against this important but extremely understudied human pathogen.

描述（由申请人提供）：人类肝炎E的致病药物乙型肝炎病毒（HEV）是发展中国家的重要公共卫生问题，在美国和其他工业化国家也是地方性的。与HEV感染相关的死亡率最高为28％。由于缺乏细胞培养和实用的动物模型系统，因此尚未了解HEV复制和发病机理的机制，针对丙型肝炎E的疫苗仍无法使用。我们最近从猪和鸡肉中发现的猪和禽类肝炎病毒，以及动物HEV菌株的跨物种感染的能力为HEV研究开辟了新的途径。乙型肝炎现在是一种公认​​的人畜共患病，猪（也许还有其他动物）是已知的储层。该提议基于我们最近发现的猪和禽类猪脉，建立用于HEV的猪和鸡模型，建造了人类，猪和鸟类HEV的传染性cDNA克隆以及支持HEV上的两个先前NIH奖项引起的HEV（AI01653，AI46505）的细胞系的鉴定。 PI决定不提交竞争性续订，以便他可以通过提交一项新提案来结合过期奖项的指示并扩大HEV研究的范围。长期目标是通过使用猪，鸡和非人类灵长类动物作为模型来了解HEV复制，发病机理和跨物种感染的机制，并使用禽类，鸟类，禽类和猪 - 人类和猪-Human HEV嵌合体来识别对这些过程在功能上重要的基因组区域。在此提案中，我们的目标是：（1）。确定高变量区域（HVR）在HEV复制和发病机理中的作用； （2）。了解HEV跨物种感染和宿主敏感性的分子基础； （3）。对HEV帽蛋白上的氨基酸残基细上图对HEV衰减很重要。这将通过使用包括细胞培养物，分子生物学和动物研究在内的标准技术来实现。拟议的研究将大大提高我们对HEV复制，发病机理和跨物种感染机制的理解，并将为未来的疫苗发育提供有用的信息。公共卫生相关性：缺乏有关HEV基本生物学和发病机理的知识极大地阻碍了针对HEV的疫苗的开发。从该项目中获得的信息将有助于了解HEV复制和发病机理的机制，并有助于设计有效的预防和控制策略（例如，实时销售疫苗），以抵抗这种重要但非常研究的人类病原体。