Mopeia/Lassa Virus Reassortants as Lassa Fever Vaccines

描述(申请人提供)：ArenaVirus是一种新出现的病原体，由啮齿动物携带，偶尔会传播给人类，造成致命后果。我们的研究主要集中在拉沙热病毒，因为它对人类的毒力。拉沙热每年造成多达30万人感染，疫情发生在流行区以外。与小鼠中已有的ArenaVirus致病模型不同，拉沙热在人、豚鼠和非人类灵长类动物中的毒力与病毒血症直接相关，与免疫介导的病理关系较小。豚鼠是阐明拉萨病毒感染的发病机制以及疫苗和治疗发展的潜在有用的模型。莫佩亚病毒是拉沙热病毒的近亲，对豚鼠和猴子没有致命性，可以保护它们免受拉沙病毒的攻击。为了确定Lassa病毒毒力的遗传基础，我们在Lassa(LAS)和Mopeia(MOP)病毒之间构建了异种病毒重组体。我们在豚鼠身上的研究表明，MOP/LAS重组体病毒与莫培氏菌一样，是一种无毒和非嗜神经性病毒，并携带LassA的主要保护性表位。我们将检验这样一种假设，即MOP/LAS重组病毒对致命性病毒攻击具有保护作用。我们的具体目标将是1)比较重组病毒与两种亲本病毒LAS和MOP对豚鼠的致病性；2)测试MOP/LAS重组体保护动物免受LAS病毒致命攻击的能力。毒力将通过存活、病毒血症、组织中的病毒载量、临床化学和血液病理变化来衡量。由于在单核/巨噬细胞和内皮细胞的体外实验显示LAS和MOP感染对IL-8和IL-8表达的不同影响，因此将监测促炎细胞/趋化因子、肿瘤坏死因子-α和IL-8。我们的长期目标是了解LAS病毒的发病机制，并开发有效的治疗方法和疫苗。

DESCRIPTION (provided by applicant): Arenaviruses are emerging pathogens that are carried by rodents and occasionally transmitted to man with lethal consequences. Our studies focus on Lassa fever virus due to its virulence for human beings. Lassa fever accounts for as many as 300,000 annual infections, and outbreaks have occurred outside the endemic area. In contrast to the well-studied model of arenavirus pathogenesis in the mouse, the virulence of Lassa fever in man, guinea pigs and non-human primates is directly related to viremia, and less related to immune-mediated pathology. Guinea pigs are a potentially useful model for elucidating the pathogenesis of Lassa virus infection and for vaccine and treatment developments. A close relative of Lassa fever virus, Mopeia virus, is not lethal for guinea pigs and monkeys and can protect them from Lassa virus challenge. To determine the genetic basis of Lassa virus virulence we made interspecies virus recombinants between Lassa (LAS) and Mopeia (MOP) viruses. Our studies in guinea pigs show that MOP/LAS reassortant virus is avirulent and non-neurotropic like Mopeia and bears the major protective epitopes of Lassa. We will test the hypothesis that MOP/LAS reassortant virus confers protection from a lethal virus challenge. Our specific aims will be to 1) compare the pathogenicity of reassortant viruses with the pathogenicity of the two parental viruses, LAS and MOP, in guinea pigs; 2) test the ability of the MOP/LAS reassortant to protect animals from lethal challenge with LAS virus. Virulence will be measured in terms of survival, viremia, viral load in tissues, disturbances in clinical chemistry and hemathology. Pro-inflammatory cyto/chemokines, TNF-a and IL-8 will be monitored because in vitro experiments in monocytes/macrophages and endothelial cells show differential effects of LAS and MOP infections on IL-8 and TNF-a expression. Our long range goal is to understand LAS virus pathogenesis and to develop effective treatment and vaccines.