MOLECULAR BASIS OF ARENAVIRUS VIRULENCE

描述（改编自申请人的摘要）：Salvato博士指出， 沙粒病毒是人类的重要病原体， 啮齿动物携带者。 这一领域的大多数研究利用原型 沙粒病毒，淋巴细胞性脉络丛脑膜炎病毒（LCMV），探索 宿主/对感染的反应和病毒发病机制。 Salvato博士完成LCMV序列有助于研究 病毒结构、调节机制和毒力决定因素。 目前的目标是扩大这些研究，包括最致命的 拉沙热病毒 拉沙热病毒的研究 由于其地理位置局限于西非， 需要使用四级防范措施 这些研究将联合收割机 分子生物学和动物模型，以获得更好的知识 拉沙热病毒的结构，宿主的免疫反应感染， 病毒毒力决定因素 具体的主题是1.完成 拉沙热病毒的基因组序列分析，2.做一个分子 通过检测Lassa基因鉴定拉沙热病毒感染 表达，抗原血症，抗体和细胞免疫反应， 感染者血液中的特异性拉沙热病毒基因产物 和豚鼠模型中，以及3.研发拉沙病毒的口服疫苗 使用豚鼠模型系统和鼠伤寒沙门氏菌的发热病毒 向量。 了解拉沙热生物学的综合方法 病毒将为防护设计建立合理的目标 疫苗。 关键信息将来自对人类的研究。 能够在自然感染中生存的生物和能够生存的豚鼠 实验性口服接种拉沙热病毒 这些实验 将在4级隔离设施中进行， 亚特兰大的疾控中心 由于其分析而生成的试剂 拉沙热病毒序列将为病毒评价提供新手段 这两个系统中的复制和主机响应。 基于这些 研究和考虑到感染的自然途径是 可能是口服，研究者决定开始接种疫苗 通过产生活的减毒重组鼠伤寒沙门氏菌的研究 表达拉沙热病毒蛋白的菌株。 这种形式的口头 疫苗应诱导对病毒的粘膜免疫，并可能具有保护性。 将在豚鼠模型系统中检测疫苗效力。 拉沙热病毒是西非的一种重要病原体， 这些研究将显著地 加强对这种剧毒物质的了解，并将试图 提供廉价的口服疫苗。

DESCRIPTION (Adapted from Applicant's Abstract): Dr. Salvato states that arenaviruses are important pathogens in man and are transmitted from wild rodent carriers. Most studies in this area utilize the prototype arenavirus, lymphocytic choriomeningitis virus (LCMV), to explore the host/response to infection and the mechanisms of viral pathogenesis. Completion of the LCMV sequence by Dr. Salvato facilitates studies of the virus structure, regulatory mechanisms, and virulence determinants. The current goal is to expand these studies to include the most virulent virus in the group, the Lassa Fever Virus. Study of Lassa Fever Virus is complicated by its geographic restriction to Western Africa and the need to use Level 4 containment precautions. The studies will combine molecular biology and animal models to obtain a better knowledge of Lassa Fever Virus structure, the host immune response infection, and viral determinants of virulence. The specific themes are 1. to complete the genomic sequence analysis of Lassa Fever Virus, 2. to do a molecular characterization of Lassa Fever Virus infection by examining Lassa gene expression, antigenemia, and antibody and cellular immune responses to specific Lassa Fever Virus gene products in the blood of infected humans and in the guinea pig model, and 3. to develop an oral vaccine for Lassa Fever Virus using the guinea pig model system and salmonella typhimurium vectors. The comprehensive approach to understanding the biology of Lassa Fever Virus will establish rational goals for the design of protective vaccines. Crucial information will derive from the studies of human beings that survive natural infection and guinea pigs that survive experimental oral inoculation of Lassa Fever Virus. These experiments with virus will be performed in Level 4 containment facilities at the CDC in Atlanta. Reagents generated in consequence of their analysis of Lassa Fever Virus sequence will provide new means for evaluating virus replication and host responses in these two systems. Based on these studies and the consideration that the natural route of infection is likely to be oral, the investigator has decided to initiate vaccine studies by generating live attenuated recombinant Salmonella typhimurium strains that express Lassa Fever Virus proteins. This form of oral vaccine should induce mucosal immunity to virus and may be protective. Vaccine efficacy will be tested in the guinea pig model system. Lassa Fever Virus is an important pathogen in West Africa and an emerging pathogen for the rest of the world.These studies will significantly enhance understanding of this highly virulent agent and will attempt to provide an inexpensive oral vaccine.