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（由申请人提供）：正痘病毒（OPV）是大型 DNA 病毒，对其天然宿主具有高度致命性。天花是由人类特异性正痘病毒天花病毒 (VARV) 产生的，通过接种活痘苗病毒 (VACV)（一种轻度致病性正痘病毒）可被根除。尽管取得了这一成功，我们仍然对 OPV 在其自然宿主中具有高致病性的原因以及天花疫苗的保护机制知之甚少。研究 OPV 对人类健康很重要，原因如下：1) OPV 在许多动物物种中很常见，其中一些病毒可能跨越物种屏障，成为人类病原体。 2) 人们担心天花病毒可能被用作武器。 3) 根据现行标准，基于活 VACV 的疫苗并不安全，灭活 VACV 也没有保护作用。 4) 由于天花疫苗非常有效，了解它如何提供保护对于开发其他病毒（包括其他大型 DNA 病毒，如疱疹病毒）的疫苗可能很有价值。在这个项目中，我们的模型将是小鼠正痘病毒（ECTV），它会在易感小鼠品系中产生小鼠痘。 OPV 的一个显着特征是它们表达分泌性免疫反应调节剂 (IRM)。在具体目标 1 中，我们将构建并表征不表达特定 IRM 的 ECTV 突变体。这些突变体将在组织培养中进行测试并与野生型病毒进行比较；它们在免疫缺陷和免疫功能正常的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 IRM 的直系同源物在其他致命的 OPV 感染（例如人类天花）中的功能。在具体目标 2 中，我们将确定暴露于病毒粒子表面的特定 IRM 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的保护性免疫机制，并测试一种非感染性抗 OPV 疫苗的新方法。