TARGETING CELLULAR PROCESSES TO INHIBIT MONKEYPOX VIRUS INFECTION IN VIVO

靶向细胞过程抑制体内猴痘病毒感染

• 批准号: 8173217
• 负责人: SCOTT W WONG
• 金额: $ 4.76万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8173217
• 关键词: African; Animals; B-Lymphocytes; Binding Proteins; CD8B1 gene; Cell physiology; Clinical; Complement; Complement Inactivators; Computer Retrieval of Information on Scientific Projects Database; Democratic Republic of the Congo; Development; Disease; Enzymes; Exhibits; Funding; Generations; Goals; Grant; Immune response; Infection; Institution; Lead; Lesion; Macaca mulatta; Modeling; Monkeypox; Monkeypox virus; Monocytosis; Pilot Projects; Play; Proteins; Recombinants; Research; Research Personnel; Resources; Role; Smallpox; Source; Staining method; Stains; Symptoms; T cell response; Temperature; United States National Institutes of Health; Viral; Virulence Factors; Virus Diseases; comparative; cytokine; in vivo; monocyte; mutant; response; tool

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This was a pilot project that supported the development of a rhesus macaque model of monkeypox virus (MPV) infection and disease. The goal was to characterize the disease course and host response to MPV infection as this had not been well characterized. During the study period, we found that animals inoculated intrabronchially with the Zaire strain of MPV exhibited clinical symptoms consistent with smallpox. Specifically, these animals exhibited widespread pox lesions, which were coincident with elevated temperatures. Immunologically, these animals exhibited robust T and B cell proliferative responses following inoculation that lead to CD4 and CD8 specific T cell responses as determined by intracellular cytokine staining. Having characterized the virological parameters and the host response to infection, we initiated comparative infection studies to define potential phenotypic differences between wild type MPV and targeted mutants of MPV. We started with a recombinant that lacks the monkeypox inhibitor of complement enzymes (MOPICE), a protein widely considered to be a virulence factor for central African strains of MPV. We compared clinical disease and host adaptive immune response following infection with MPXV-Zaire, or recombinant MPXV-Zaire lacking expression of MOPICE. Interestingly, the loss of MOPICE expression results in enhanced viral replication in vivo, as well as a dampened adaptive immune response against MPXV. Taken together these findings suggest that MOPICE plays an important role in the generation of the anti-MPXV immune response, and that this protein is not the sole virulence factor of the Central African clade of MPXV. During the past year we evaluated the pathogenic potential of a recombinant MPV that lacks the viral encoded complement binding protein (vCBP), a protein widely considered to be a virulence factor for central African strains of MPV. This recombinant MPV will enable us to definitively determine if vCBP is necessary for MPV-associated disease. This provides a unique tool to define whether circulating monocytes in MPV-infected animals presenting with monocytosis are MPV-infected.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 这是一个试点项目，支持开发猴痘病毒（MPV）感染和疾病的恒河猴模型。目标是描述疾病病程和宿主对 MPV 感染的反应，因为这一点尚未得到很好的描述。在研究期间，我们发现支气管内接种 MPV 扎伊尔株的动物表现出与天花一致的临床症状。具体来说，这些动物表现出广泛的痘损伤，这与气温升高同时发生。在免疫学上，这些动物在接种后表现出强烈的 T 和 B 细胞增殖反应，导致 CD4 和 CD8 特异性 T 细胞反应（通过细胞内细胞因子染色确定）。在确定了病毒学参数和宿主对感染的反应后，我们启动了比较感染研究，以确定野生型 MPV 和 MPV 靶向突变体之间潜在的表型差异。我们从缺乏猴痘补体酶抑制剂 (MOPICE) 的重组体开始，MOPICE 是一种被广泛认为是中非 MPV 毒株毒力因子的蛋白质。我们比较了 MPXV-Zaire 或缺乏 MOPICE 表达的重组 MPXV-Zaire 感染后的临床疾病和宿主适应性免疫反应。有趣的是，MOPICE 表达的丧失导致体内病毒复制增强，以及针对 MPXV 的适应性免疫反应减弱。总而言之，这些发现表明 MOPICE 在抗 MPXV 免疫反应的产生中发挥着重要作用，并且该蛋白并不是中非 MPXV 分支的唯一毒力因子。 去年，我们评估了缺乏病毒编码的补体结合蛋白（vCBP）的重组 MPV 的致病潜力，这种蛋白被广泛认为是中非 MPV 毒株的毒力因子。这种重组 MPV 将使我们能够明确确定 vCBP 是否是 MPV 相关疾病所必需的。这提供了一种独特的工具来确定表现出单核细胞增多症的 MPV 感染动物中的循环单核细胞是否感染 MPV。