Role of the E3L gene in poxvirus pathogenesis

本建议的目的是了解一种主要的牛痘病毒干扰素的功能 （干扰素）抗性和神经毒力基因，E3 L。由于VV是天花疫苗， 生物战/生物恐怖主义制剂，对这种毒力因子的分析可能会导致开发更安全， 预防生物恐怖袭击的有效疫苗。此外，这些更安全，更有效的菌株 VV作为通用疫苗载体的应用可能有价值。由于E3 L基因高度 在VV和天花病毒的所有毒株之间是保守的，天花的病原体，这项工作可以 导致抗天花药物的发展。本建议中所述的工作将继续进行 研究确定E3 L编码蛋白的生化特征所起的作用 以躲避VV的宿主防御突变体分别影响每个已知的生化 将制备和表征与E3 L编码的蛋白质相关的特征。这些阱 然后，将使用表征的突变体来确定每个生化特征的作用， E3 L在每种已知的E3 L生物学功能中的作用，包括在小鼠模型中的发病机制。 将获得抑制突变并分析E3 L中的特定突变。E3 L系统是 在允许从分子水平分析这一重要毒力基因的功能方面是独一无二的。 整个动物的发病水平。因此，这项工作将导致基本分子的翻译 将E3 L功能知识应用于临床相关应用。

The Aim of this proposal is to understand the function of one of the major vaccinia virus (W) interferon (IFN)-resistance and neurovirulence genes, E3L. Since VV is the vaccine for smallpox, a potential biowarfare/bioterrorism agent, analysis of this virulence factor may lead to development of safer, more effective vaccines for defense against bioterrorism attacks. In addition, these safer, more effective strains of VV may be valuable for use of VV as a general vaccine vector. Since the E3L gene is highly conserved between VV and all strains of variola virus, the causative agent of smallpox, this work may lead to development of anti-smallpox drugs. The work described in this proposal will continue investigations into defining the roles that the biochemical characteristics of the E3L-encoded proteins play in evasion of the host defenses by VV. Mutants that separately affect each of the known biochemical characteristics associated with E3L-encoded proteins will be prepared and characterized. These well characterized mutants will then be used to determine the role of each of the biochemical characteristics of E3L in each of the known biological functions of E3L, including pathogenesis in the mouse model.Finally, suppressor mutations will be obtained and analyzed for specific mutations in E3L. The E3L system is unique in allowing analysis of the function of this important virulence gene from the molecular level to the level of pathogenesis in a whole animal. Thus, this work will lead to translation of basic molecular knowledge of E3L function into clinically relevant applications.