Viral factors responsible for Lassa virus pathogenicity

项目摘要/摘要 这一职业发展奖将有助于填补风险的基础病毒学研究的知识和技能。 第4组试剂，需要在最高遏制实验室(BSL-4)处理。这对以下各项至关重要 目标是成为一名独立研究员，成为高致病性传染病专家。目标是 旨在通过体内和体外实验揭示拉沙热(LF)的新机制 技术，导致对发展对策和控制方法的新见解 拉沙热。 拉萨病毒(LASV)在西非国家流行，每年都会导致LF暴发。虽然LASV 从公共卫生的角度来看，是最令人担忧的病原体之一，几乎没有有效的疫苗或 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的动物模型是有限的，这对于基础研究和开发对策是必不可少的。 最近，我们建立了一种新的豚鼠LF模型，发现LASV株LF2384和LF2350具有 豚鼠完全不同的致病表型。这两种病毒是从人类身上分离出来的。 LF患者和这些病毒在豚鼠中的致病性与人类病例一致。这些独特的 结合免疫活性啮齿动物模型和临床分离的LASV是强有力的工具，使我们能够 揭示病毒致病因子和LASV致病的分子机制。在……里面 在这项拟议的研究中，我们将确定导致LASV致病的因素并揭示新的分子 用反向遗传学、体内实验和几种体外实验研究LASV感染的机制 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，我们将确定导致LASV的病毒因素 利用反向遗传学和体内研究的致病性。在具体目标3中，我们将揭示分子机制 潜在的LASV致病性。综上所述，我们希望解决LASV的新致病机制 感染，导致了新的见解，以制定应对措施。

PROJECT SUMMARY/ABSTRACT This career development award will help fill in the knowledge and skills in basic virological research of Risk Group 4 agents, which need to be handled in the highest containment laboratory (BSL-4). This is essential for the goal to become an independent researcher as an expert on highly pathogenic infectious diseases. The goal during the award period is to reveal novel mechanisms of Lassa fever (LF) by using both in vivo and in vitro techniques, leading to new insight into the development of countermeasures and controlling methods against Lassa fever. 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. In the proposed study, we will determine factors responsible for LASV pathogenicity and reveal novel molecular mechanisms underlying LASV infection by using reverse genetics, in vivo experiments, and 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 viral factors 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.