Orthropoxvirus Pathogenesis and Vaccines

正痘病毒发病机制和疫苗

• 批准号: 8073229
• 负责人: Luis J Sigal
• 金额: $ 2.13万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8073229
• 关键词: Affect; Animals; Antibodies; Antibody-mediated protection; Antigen Presentation; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Bone Marrow; CD8B1 gene; Cells; Code; DNA Viruses; Disease; Disease Resistance; Fright; Gene Targeting; Genes; Growth; Health; Herpesviridae; Histocompatibility Antigens Class I; Human; Immune Sera; Immune response; Immunity; Immunization; Immunocompetent; Infection; Infectious Ectromelia; Integration Host Factors; Interferon-alpha; Interferons; Interleukin-18; Life; Macaca mulatta; Memory; Modeling; Monkeypox virus; Morbidity - disease rate; Mouse Pox Virus; Mouse Strains; Mus; Mutation; Orthologous Gene; Orthopoxvirus; Pathogenesis; Pathogenicity; Pathology; Production; Proteins; Recombinants; Research Personnel; Resistance; Role; Smallpox; Smallpox Vaccine; Smallpox Viruses; Structural Protein; Subunit Vaccines; Surface; T cell response; T-Lymphocyte; Testing; Time; Vaccination; Vaccines; Vaccinia virus; Viral; Viral Antigens; Viral Proteins; Virion; Virus; Virus Diseases; Virus Receptors; Work; base; env Gene Products; experience; interleukin-18 binding protein; killings; mortality; mutant; novel strategies; pathogen; prevent; programs; receptor; research study; response; success; tissue culture; weapons

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(申请人提供)：正痘病毒(OPV)是一种对其自然宿主具有高度致命性的大型DNA病毒。天花是由人类特有的OPV天花病毒(VARV)产生的，并通过接种活牛痘病毒(VACV)根除，VACV是一种轻度致病的OPV。尽管取得了这一成功，但我们仍然对OPV在其自然宿主中高致病性的原因以及天花疫苗保护作用的机制知之甚少。研究OPV对人类健康具有重要意义，原因有几个：1)OPV在许多动物物种中都很常见，其中一些病毒可以跨越物种屏障，成为人类的病原体。2)人们担心VARV可能被用作武器。3)以活VACV为基础的疫苗按现行标准是不安全的，灭活VACV没有保护作用。4)由于天花疫苗是如此有效，了解它是如何保护的可能对开发针对其他病毒的疫苗很有价值，包括其他大型DNA病毒，如疱疹病毒。在这个项目中，我们的模型将是小鼠OPV ectromelia病毒(ECTV)，它会在易感品系的小鼠中产生鼠痘。OPV的一个显著特征是它们表达分泌型免疫反应修饰物(IRMS)。在特定目标1中，我们将构建和鉴定不表达特定IRM的ECTV突变体。这些突变体将被测试并与野生型病毒进行比较，以了解它们在组织培养中的生长情况，它们在免疫缺陷和免疫活性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。任何发现都应该适用于这些IRMS的同源基因在其他致命的OPV感染中的功能，例如人类的天花。在具体目标2中，我们将确定暴露在病毒粒子表面的特定IRMS和结构蛋白是否是保护性免疫反应的天然目标，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诱导保护性免疫的机制，并测试一种非传染性抗OPV疫苗的新方法。