Role of the E3L gene in poxvirus pathogenesis

描述（由申请方提供）：本提案的目的是了解主要牛痘病毒（VV）干扰素（IFN）抗性和神经毒力基因之一E3 L的功能。由于VV是天花的疫苗，天花是一种潜在的生物战/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，更有效的疫苗来防御生物恐怖主义袭击。此外，这些更安全、更有效的VV毒株可能对VV用作通用疫苗载体有价值。由于E3 L基因在VV和天花病毒（天花的病原体）的所有毒株之间高度保守，因此这项工作可能会导致抗天花药物的开发。本提案中描述的工作将继续研究确定E3 L编码蛋白的生化特征在VV逃避宿主防御中发挥的作用。将制备并表征分别影响与E3 L编码蛋白相关的每种已知生化特征的突变体。然后将这些充分表征的突变体用于确定E3 L的每个生化特征在E3 L的每个已知生物学功能中的作用，包括小鼠模型中的发病机制。最后，将获得抑制突变并分析E3 L中的特定突变。E3 L系统的独特之处在于可以从分子水平到整个动物的发病机制水平分析这一重要毒力基因的功能。因此，这项工作将导致翻译的基本分子知识E3 L功能的临床相关应用。

DESCRIPTION (provided by applicant): The Aim of this proposal is to understand the function of one of the major vaccinia virus (VV) 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.