Mopeia/Lassa Virus Reassortants as Lassa Fever Vaccines

描述（由申请方提供）：沙粒病毒是一种由啮齿动物携带的新出现的病原体，偶尔会传播给人类并造成致命后果。由于拉沙热病毒对人类的毒性，我们的研究重点放在拉沙热病毒上。拉沙热每年的感染人数多达30万，在流行区以外也发生过疫情。与沙粒病毒在小鼠中发病机制的充分研究模型相反，拉沙热在人、豚鼠和非人灵长类动物中的毒力与病毒血症直接相关，与免疫介导的病理学相关性较小。 豚鼠是阐明拉沙病毒感染的发病机制以及疫苗和治疗开发的潜在有用模型。 拉沙热病毒的近亲莫佩亚病毒对豚鼠和猴子不致命，可以保护它们免受拉沙热病毒的攻击。为了确定拉沙病毒毒力的遗传基础，我们在拉沙（LAS）和莫佩亚（MOP）病毒之间进行了种间病毒重组。我们在豚鼠中的研究表明，MOP/LAS防御病毒与Mopeia一样是无毒力和非嗜神经性的，并且具有Lassa的主要保护性表位。我们将检验MOP/LAS抗性病毒对致死性病毒攻击具有保护作用的假设。我们的具体目标是：1）在豚鼠中比较重组病毒的致病性与两种亲本病毒LAS和MOP的致病性; 2）检测MOP/LAS重组病毒保护动物免受LAS病毒致死性攻击的能力。 毒力将根据存活率、病毒血症、组织中的病毒载量、临床化学和血液病理学紊乱来测量。将监测促炎细胞/趋化因子、TNF-a和IL-8，因为单核细胞/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TNF-a表达的不同影响。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.