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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 这是一个支持开发猴痘病毒（MPV）感染和疾病的恒河猴模型的试点项目。目的是表征疾病过程和宿主对MPV感染的反应，因为这还没有得到很好的表征。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。具体而言，这些动物表现出广泛的痘病变，这与温度升高一致。在免疫学上，这些动物在接种后表现出稳健的T和B细胞增殖应答，导致通过细胞内细胞因子染色确定的CD 4和CD 8特异性T细胞应答。在表征了病毒学参数和宿主对感染的反应后，我们开始了比较感染研究，以确定野生型MPV和靶向MPV突变体之间的潜在表型差异。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。我们比较了感染MPXV-Zaire或缺乏MOPICE表达的重组MPXV-Zaire后的临床疾病和宿主适应性免疫应答。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的适应性免疫应答减弱。总之，这些发现表明，MOPICE在产生抗MPXV免疫应答中起着重要作用，并且这种蛋白质不是MPXV中非分支的唯一毒力因子。 在过去的一年中，我们评估了一种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。这提供了一个独特的工具，以确定是否循环单核细胞在MPV感染的动物呈现单核细胞增多症的MPV感染。