IMMUNOSUPPRESION BY MEASLES & CANINE DISTEMPER VIRUSES

麻疹引起的免疫抑制

• 批准号: 8357267
• 负责人: ROBERTO B. CATTANEO
• 金额: $ 7.56万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357267
• 关键词: Acute; Animal Model; Animals; Back; Biological Assay; CD46 Antigen; California; Canine Distemper; Canine Distemper Virus; Canis familiaris; Cattle; Cells; Complement Activation; Complementary DNA; Complex; Defective Viruses; Depressed mood; Disease; Ferrets; Funding; Grant; Human; Immune; Immune response; Immunosuppression; Immunosuppressive Agents; In Vitro; Infection; Interferon Activation; Lymphatic; Macaca; Measles; Morbillivirus; Mutation; National Center for Research Resources; Organ; Outcome; Peripheral Blood Mononuclear Cell; Phosphorylation; Play; Primates; Principal Investigator; Proteins; Recombinants; Relative (related person); Research; Research Infrastructure; Resources; Rinderpest; Rinderpest virus; Role; SLAM protein; STAT protein; Source; Staging; System; Testing; Tuberculin Test; United States National Institutes of Health; Vaccines; Viremia; Virulence; Virus; Virus Receptors; White Blood Cell Count procedure; base; blind; cell type; citrate carrier; cost; cytokine; lymphocyte proliferation; neutralizing antibody; receptor; research study; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Measles is the disease with which the phenomenon of virus-induced immunosuppression was discovered: in 1908 von Pirquet observed that the tuberculin skin test response was transiently depressed during the course of acute measles. Morbilliviruses including measles (MV), canine distemper (CDV) and rinderpest are immunosuppressive. The mechanisms underlying this phenomenon are complex, but viral receptor interactions may play a central role: wild-type MV, CDV and rinderpest virus strains preferentially use the immune cell-specific protein SLAM (human, canine or bovine, respectively) as a receptor. In addition, the MV vaccine strain Edmonston enters cells preferentially also through the ubiquitous regulator of complement activation, CD46, and CD46 interactions modify the immune response to MV. Moreover, post-entry host control evasion mechanisms elicited by the MV non-structural proteins V and C interfere with STAT protein phosphorylation and interferon activation. We will test two hypotheses: first, that SLAM-dependant entry is of central importance for immunosuppression by morbilliviruses. Second, that the V and C proteins favor virus dissemination in immune cells and systemically. Two animal models will be used: macaques for measles and ferrets for canine distemper. We have produced selectively receptor-blind recombinant MVs and CDVs. We are constructing wild type-derived MVs and CDVs in which the expression of V or C, or of both proteins, is silenced or enhanced. Macaques or ferrets will be infected intranasally and the cell types supporting MV and CDV dissemination in PBMC, and in lymphatic and non-lymphatic organs, will be identified. Virulence and immunosuppression will be characterized based on graded parameters including disease signs, leukocyte number, strength and duration of viremia, in vitro lymphocyte proliferation levels, neutralizing antibody liters, and cytokine profile. We predict differential changes in these parameters following infections with viruses defective at the receptor recognition or post-entry level. Results will be interpreted in the context of these predicted outcomes. Candidate mutations for reversion to virulence will be sought in viruses replicating at late disease stages based on functional assays, sequencing, and back-transfer in infectious cDNAs. These experiments will define the relative importance of cell entry through specific receptors and of post-entry host control evasion mechanisms for morbillivirus-induced immunosuppression in two biologically relevant animal systems.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 麻疹是发现了病毒诱导的免疫抑制现象的疾病：1908年，冯·皮尔克特（Von Pirquet）观察到结核蛋白皮肤测试反应在急性麻疹过程中暂时降低。包括麻疹（MV），犬静止（CDV）和Rinderpest在内的虫比病毒是免疫抑制的。该现象的基础机制很复杂，但是病毒受体相互作用可能起着核心作用：野生型MV，CDV和Rinderpest病毒菌株优先使用免疫细胞特异性蛋白质SLAM（分别为人类，犬类或牛）作为受体。此外，MV疫苗菌株Edmonston也通过无处不在的补体激活，CD46和CD46相互作用的无处不在的调节器来优先进入细胞，这会改变对MV的免疫反应。此外，MV非结构性蛋白质V和C引起的进入后宿主控制逃避机制干扰了Stat蛋白磷酸化和干扰素激活。我们将检验两个假设：首先，该依赖的依赖性依赖性对伪病毒的免疫抑制至关重要。其次，V和C蛋白在免疫细胞和系统中偏爱病毒传播。将使用两种动物模型：麻疹和雪貂的猕猴。我们已经产生了有选择性的受体重组MV和CDV。我们正在构建野生型MV和CDV，其中V或C或两种蛋白的表达被沉默或增强。猕猴或雪貂将被鼻内感染，并在PBMC中支持MV和CDV传播的细胞类型，以及在淋巴和非淋巴器官中。毒力和免疫抑制作用将根据分级参数（包括疾病体征，白细胞数，强度和病毒血症的持续时间），体外淋巴细胞增殖水平，中和抗体脂肪和细胞因子的特征来表征。我们预测在受体识别或入学后感染病毒有缺陷后，这些参数的差异变化。结果将在这些预测结果的背景下进行解释。在疾病晚期，基于功能分析，测序和反传染性cDNA中的反向转移，将寻求在疾病晚期复制的病毒中的候选突变。这些实验将定义通过特定受体进入细胞进入的相对重要性，以及在两个生物学相关的动物系统中，针对病毒诱导的病毒诱导的免疫抑制的宿主控制逃避机制的相对重要性。