MOLECULAR BASIS OF ARENAVIRUS VIRULENCE

描述(改编自申请者摘要)：塞尔瓦托博士表示 禽流感病毒是人类的重要病原体，由野生动物传播。 啮齿动物携带者。这一领域的大多数研究都是利用原型 ArenaVirus，淋巴细胞性脉络膜脑膜炎病毒(LCMV) 宿主/对感染的反应和病毒致病机制。 塞尔瓦托博士完成LCMV序列有助于研究 病毒结构、调控机制和毒力决定因素。 目前的目标是将这些研究扩大到包括最致命的 集团中的病毒，拉沙热病毒。拉沙热病毒的研究 因其地理位置局限于西非和 需要使用4级安全壳预防措施。这些研究将结合 分子生物学和动物模型，以更好地了解 拉沙热病毒结构，宿主免疫反应感染，以及 毒力的病毒决定因素。具体的主题是：1.完成 拉沙热病毒基因组序列分析，2.做分子 检测LassA基因鉴定拉沙热病毒感染特征 表达、抗原血症、抗体和细胞免疫反应 感染人群血液中特异的拉沙热病毒基因产物 在豚鼠模型中，以及3.开发拉沙病毒口服疫苗 利用豚鼠模型系统和鼠伤寒沙门氏菌建立发热病毒模型 向量。 了解拉沙热生物学的综合方法 病毒将为防护设计确立合理的目标 疫苗。关键信息将来自对人类的研究 在自然感染中存活的生物和存活下来的豚鼠 实验性口服接种拉沙热病毒。这些实验 将在4级遏制设施中进行病毒检测 亚特兰大疾控中心。产生的试剂是由于他们分析了 拉沙热病毒序列将为评估病毒提供新的手段 这两个系统中的复制和主机响应。基于这些 研究认为，感染的自然途径是 很可能是口服的，研究人员决定开始接种疫苗 重组鼠伤寒沙门氏菌减毒活菌的研究 表达拉沙热病毒蛋白的菌株。这种形式的口语 疫苗应诱导对病毒的粘膜免疫，并可能具有保护性。 疫苗效力将在豚鼠模型系统中进行测试。 拉沙热病毒是西非的一种重要病原体和一种新兴的 世界上其他地方的病原体。这些研究将显著 加强对这种高毒力病原体的了解，并将尝试 提供一种廉价的口服疫苗。

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.