Mechanism of Lassa fever virus Z protein in immune suppression and viral virulence

摘要 拉沙热病毒Z蛋白的免疫抑制和病毒毒力机制 拉沙热病毒(LASV)是引起地方性和致死性疾病的最重要的病毒病原体。 西非人类中的出血热每年造成数千人死亡。进口LASV 由于人类旅行的增加，美国和其他西部国家的感染情况一再被记录下来 往返于疫区国家。目前还没有针对LASV的疫苗和有限的治疗选择。 在LASV感染者中，疾病严重程度存在显著的异质性，范围从 多器官衰竭和死亡的无症状感染，原因不明，但部分原因可能是 由于LASV分离株的不同，其序列变异高达32%。LASV的分子决定因素 致死性尚不清楚。LASV的发病机制尚不清楚，但与一般的 宿主免疫抑制，其特征是缺乏早期的先天免疫反应 有效的适应性免疫。我们工作的长期目标是了解LASV的机制 毒力和疾病发病机制，以开发急需的疫苗和抗病毒药物。我们有 最近发现了几种已知的致病Arena病毒(包括 LASV)抑制人RIG-I样受体(RLRs)RIG-I和MDA5，这两个受体是 RNA病毒。我们还获得了初步证据表明，来自不同LASV的Z蛋白 不同的菌株抑制RLRs的能力不同。此外，我们还证明了这种Z-介导的RLR结合和 抑制是物种特有的，这可能解释了不同物种在疾病发病机制上的差异。 动物物种。我们假设LASV Z蛋白对RLRs的病毒和宿主依赖性抑制是一种 新的毒力决定因素，并提出以下目的是为了验证这一假说。 目的1：剖析LASV Z介导的RLR抑制的分子机制。 目的：确定LASV Z介导的RLR抑制在病毒毒力中的生物学作用。 目的：探讨LASV Z介导的RLR抑制的种属特异性机制。 这些研究集中在LASV Z介导的一种新的免疫抑制和毒力机制 蛋白质，这不仅将对阿拉伯病毒的基础研究和翻译研究产生重大影响 病原体，但也提供了关于宿主-病原体相互作用、宿主抗病毒反应和病毒的新知识 免疫逃避机制。

Abstract Title: Mechanism of Lassa fever virus Z protein in immune suppression and viral virulence Lassa fever virus (LASV) is the most significant arenavirus pathogen that causes endemic and lethal hemorrhagic fever (HF) in humans in West Africa with thousand of death annually. Importation of LASV infection to USA and other Western counties has been repeatedly documented due to increased human travel to and from the endemic countries. Currently there is no vaccine and limited treatment options against LASV. Among LASV-infected individuals, there are significant heterogeneity in disease severity, which ranges from asymptomatic infections to multi-organ failure and death, the reason for which is unknown but may partly be due to the different LASV isolates that show sequence variations up to 32%. Molecular determinants for LASV virulence remain unknown. LASV pathogenesis has not been well understood but is associated with a general host immune suppression that is characterized by the lack of early innate immune responses and the absence of effective adaptive immunity. The long-term goal of our work is to understand the mechanisms of LASV virulence and disease pathogenesis in order to develop the much-needed vaccines and antivirals. We have recently discovered a unique ability of the Z protein of several known pathogenic arenaviruses (including LASV) to inhibit the human RIG-i-like receptors (RLRs) RIG-i and MDA5, which are the intracellular sensors of RNA viruses. We have also obtained preliminary evidence to show that the Z proteins from different LASV isolates vary in their ability to inhibit RLRs. In addition, we show that this Z-mediated RLR binding and inhibition is species specific, which may explain the observed differences in disease pathogenesis in different animal species. We hypothesize that the virus- and host-dependent inhibition of RLRs by LASV Z proteins is a novel virulence determinant and propose the following aims to test this hypothesis. Aim 1: Dissect the molecular mechanism of LASV Z-mediated RLR inhibition. Aim 2: Determine the biological role of LASV Z-mediated RLR inhibition in viral virulence. Aim 3: Investigate the species-specific mechanism of LASV Z-mediated of RLR inhibition. These studies focus on a novel immune suppressive and virulent mechanism mediated by LASV Z protein, which will not only make major impacts on both basic and translational research of arenavirus pathogens, but also provide new knowledge in host-pathogen interactions, host antiviral responses, and viral immune evasion mechanisms.