Viral factors responsible for Lassa virus pathogenicity

拉沙病毒致病性的病毒因素

• 批准号: 10815139
• 负责人: Junki Maruyama
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-05 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10815139
• 关键词: Viral; factors; responsible; Lassa; virus

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.

拉沙病毒（LASV）是西非国家的地方病，每年导致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 或治疗LF的药物。由于LASV的高致病性，必须在生物安全级别4（BSL-4）下处理。 这是发展预防或治疗LF方法的最大障碍之一。 此外，LF的动物模型有限，这对于基础研究和开发 对策最近，我们建立了一种新的LF豚鼠模型，发现LASV株LF 2384 和LF 2350在豚鼠中具有完全不同的致病表型。这两种病毒 分离自人LF患者，这些病毒在豚鼠中的致病性与人LF患者一致。 例免疫活性啮齿动物模型和临床分离的LASV的这些独特组合是强的 工具，使我们能够揭示负责致病性和分子机制的病毒因子 潜在的LASV致病性。 在K99期，我们发现依赖于RNA的RNA聚合酶（L）是K99期细胞增殖的决定因素。 利用反向遗传系统和体内试验对LASV LF 2384和LF 2350的致病性差异进行了研究 评价虽然在确定致病性病毒因素方面取得了重大进展， 了解与LASV发病机制相关的宿主反应。因此，在建议的研究中，我们会 通过反向遗传学和体内实验确定负责LASV致病性的宿主因子， 并利用几种分子生物学技术揭示了LASV L蛋白在LASV致病中的新分子机制。 体外分子技术。 我们将通过三个具体目标来实现这一目标。在具体目标1中，我们将揭示 豚鼠中的LASV感染。在具体目标2中，我们将确定L中的结构域或氨基酸残基 通过反向遗传学和体内研究，发现LASV致病性的主要机制是什么。在具体目标3中，我们 揭示LASV致病性的分子机制。总之，我们希望解决小说 LASV感染的致病机制，导致新的见解，以制定针对LF的对策。