Orthropoxvirus Pathogenesis and Vaccines

正痘病毒发病机制和疫苗

• 批准号: 7150562
• 负责人: Luis J Sigal
• 金额: $ 59.7万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7150562
• 关键词: Poxviridae; Poxviridae disease; active immunization; human; immune response; immunity; infection; model; mutant; pathology; proteins; receptor; vaccinia virus; virion

DESCRIPTION (provided by applicant): Orthopoxviruses (OPVs) are large DNA viruses that can be highly lethal to their natural hosts. Smallpox was produced by the human-specific OPV variola virus (VARV) and was eradicated through vaccination with live vaccinia virus (VACV), a mildly pathogenic OPV. Despite this success, we still know little about the reasons for the high pathogenicity of OPVs in their natural hosts and the mechanisms whereby the smallpox vaccine protects. Studying OPVs is important for human health for several reasons: 1) OPVs are common in many animal species and some of these viruses could jump the species barrier and become human pathogens. 2) There is fear that VARV could be used as a weapon. 3) The vaccine based on live VACV is not safe by current standards and killed VACV does not protect. 4) Since the smallpox vaccine is so effective, understanding how it protects may be valuable to develop vaccines to other viruses, including other large DNA viruses such as herpesviruses. In this project our model will be the mouse OPV ectromelia virus (ECTV) that produces mousepox in susceptible strains of mice. A notable feature of OPVs is their expression of secreted immune response modifiers (IRMs). In Specific Aim 1 we will construct and characterize ECTV mutants that do not express specific IRMs. These mutants will be tested and compared with wild type virus for their growth in tissue culture; their ability to spread and induce pathology in immunodeficient and immunocompetent mice; and the strength and type of humoral and cellular immune response that they induce. Any findings should be applicable to the function of the orthologs of those IRMs in other lethal OPV infections such as smallpox in humans. In Specific Aim 2, we will determine whether specific IRMs and structural proteins exposed to the surface of virions are natural targets of protective immune responses and whether they can be used as vaccines. These experiments are important because they will dissect the mechanisms of protective immunity induced by infection and test a novel approach to non-infectious anti-OPV vaccines.

描述（由申请人提供）：正托病毒（OPV）是大型DNA病毒，对其自然宿主可能是高度致命的。天花是由人类特异性OPV Variola病毒（VARV）产生的，并通过用活疫苗病毒（VACV）（一种轻度致病性OPV）通过疫苗接种来消除。尽管取得了成功，但我们仍然对OPV在天然宿主中高致病性的原因以及天花疫苗保护的机制知之甚少。研究OPV对于人类健康很重要，原因是：1）OPV在许多动物物种中很常见，其中一些病毒可能会跳跃物种障碍并成为人类病原体。 2）担心VARV可以用作武器。 3）根据当前标准，基于实时VAVV的疫苗并不安全，VAVV不能保护。 4）由于天花疫苗是如此有效，因此了解它如何保护其对其他病毒的疫苗（包括其他大型DNA病毒，例如疱疹病毒）可能是有价值的。在这个项目中，我们的模型将是小鼠OPV胚胎病毒（ECTV），该病毒（ECTV）在易感小鼠菌株中产生菌丝。 OPV的一个显着特征是它们表达了分泌的免疫反应修饰剂（IRMS）。在特定目标1中，我们将构建和表征不表达特定IRM的ECTV突变体。这些突变体将进行测试，并与野生型病毒在组织培养中的生长进行比较。它们在免疫缺陷和免疫能力小鼠中传播和诱导病理的能力；以及它们诱导的体液和细胞免疫反应的强度和类型。任何发现都应适用于其他致命的OPV感染中这些IRM的直系同源物的功能，例如人类天花。在特定目标2中，我们将确定暴露于病毒体表面的特定IRM和结构蛋白是否是保护性免疫反应的自然靶标，以及它们是否可以用作疫苗。这些实验很重要，因为它们将剖析感染引起的保护性免疫的机制，并测试一种新的非感染抗OPV疫苗的方法。