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; 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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 这是一个试点项目，该项目支持蒙基毒病毒（MPV）感染和疾病的恒河猴猕猴模型的发展。目的是表征疾病病程和宿主对MPV感染的反应，因为这尚未得到很好的特征。在研究期间，我们发现，用扎伊尔菌株在内部接种了MPV菌株的动物表现出与天花一致的临床症状。具体而言，这些动物表现出广泛的痘病变，与温度升高相吻合。从免疫学上讲，这些动物在接种后表现出强大的T和B细胞增殖反应，从而导致CD4和CD8特异性T细胞反应，由细胞内细胞因子染色确定。在表征了病毒学参数和对感染的宿主反应之后，我们开始了比较感染研究，以定义野生型MPV和MPV靶向突变体之间的潜在表型差异。我们从缺乏补体酶抑制剂（Mopice）的重组开始，该蛋白被广泛认为是中非MPV菌株的毒力因子。我们比较了MPXV-Zaire感染后的临床疾病和宿主适应性免疫反应，或者是缺乏摩托车表达的重组MPXV-Zaire。有趣的是，摩托足的丧失表达导致体内病毒复制增强，以及对MPXV的抑制自适应免疫反应。综上所述，这些发现表明，摩托足球在抗MPXV免疫反应的产生中起着重要作用，并且该蛋白质不是MPXV中非中部枝的唯一毒力因子。 在过去的一年中，我们评估了缺乏病毒编码补体结合蛋白（VCBP）的重组MPV的致病潜力，该蛋白被广泛认为是中非MPV菌株的毒力因子。这种重组MPV将使我们能够确定确定VCBP是否需要MPV相关疾病。这提供了一种独特的工具来定义具有单核细胞增多的MPV感染动物中的循环单核细胞。