Viral factors responsible for Lassa virus pathogenicity

拉萨病毒(LASV)在西非国家流行，每年都会导致LF暴发。虽然 从公共卫生的角度来看，LASV是最令人担忧的病原体之一，几乎没有有效的疫苗 或者是针对LF的治疗。由于其高度致病性，必须在生物安全级别4(BSL-4)处理LASV。 这是开发针对LF的预防或治疗方法的最大障碍之一。 此外，Lf的动物模型有限，这对Lf的基础研究和开发至关重要。 对策。最近，我们建立了一种新的豚鼠肝功能衰竭模型，发现LASV株LF2384 LF2350和LF2350在豚鼠中具有完全不同的致病表型。这两种病毒已经被 从人肝功能衰竭患者中分离到这些病毒，其对豚鼠的致病性与人类一致 案子。这些具有免疫活性的啮齿动物模型和临床分离的LASV的独特组合是强大的 工具，使我们能够揭示导致致病性的病毒因素和分子机制 潜在的LASV致病性。 在K99期，我们揭示了核糖核酸依赖的核糖核酸聚合酶(L)是 利用反向遗传系统研究LASV LF2384和LF2350的致病差异及体内差异 评估。虽然在确定致病病毒因素方面取得了重大进展，但远未取得进展。 了解与LASV致病相关的宿主反应。因此，在拟议的研究中，我们将 用反向遗传学和体内实验确定与LASV致病有关的宿主因素， 并用多种分子生物学方法揭示了蓝斑综合症病毒L蛋白致病的新分子机制 体外分子技术。 我们将通过三个具体目标来解决这一目标。在特定的目标1，我们将揭示的病理生理学 豚鼠LASV感染。在具体目标2中，我们将确定L的结构域或氨基酸残基(S) 利用反向遗传学和体内研究对LASV的致病性负责。在具体目标3中，我们将 揭示LASV致病的分子机制。综上所述，我们希望解决小说 LASV感染的致病机制，为制定防治LF的对策提供了新的见解。

Lassa virus (LASV) is endemic in West African countries and causes outbreaks of LF annually. Although LASV is one of the most alarming pathogens from a public health perspective, there are few effective vaccines or therapeutics against LF. LASV must be handled at biosafety level 4 (BSL-4), due to its high pathogenicity. This is one of the largest barriers to the development of preventive or therapeutic approaches against LF. Furthermore, animal models of LF are limited, which is essential for basic research and development of countermeasures. Recently, we developed a novel guinea pig model of LF and found that LASV strain LF2384 and LF2350 have completely different pathogenic phenotypes in guinea pigs. These two viruses have been isolated from human LF patients and pathogenicity of these viruses in guinea pigs is consistent with human cases. These unique combinations of immunocompetent rodent model and clinical isolated LASVs are strong tools, which allow us to reveal viral factors responsible for pathogenicity and molecular mechanisms underlying LASV pathogenicity. During K99 phase, we revealed that RNA-dependent RNA polymerase (L) is the determinant factor of pathogenic differences between LASV LF2384 and LF2350 by using the reverse genetic system and in vivo evaluation. While significant progress has been made in determining the pathogenic viral factor, much less is understood about the host response related to LASV pathogenesis. Therefore, in the proposed study, we will determine host factors responsible for LASV pathogenicity by using reverse genetics and in vivo experiments, and reveal novel molecular mechanisms of LASV L protein underlying LASV pathogenesis by using several in vitro molecular techniques. We will address this goal through three specific aims. In Specific Aim 1, we will reveal the pathophysiology of LASV infection in guinea pigs. In Specific Aim 2, we will determine the domain or amino acid residue(s) in L responsible for LASV pathogenicity by using reverse genetics and in vivo study. In Specific Aim 3, we will unveil molecular mechanisms underlying LASV pathogenicity. Taken together, we hope to address novel pathogenic mechanisms of LASV infection, leading to new insights to develop countermeasures against LF.