Immunosuppresion by Measles & Canine Distemper Viruses

麻疹的免疫抑制

• 批准号: 7072267
• 负责人: ROBERTO B. CATTANEO
• 金额: $ 44.24万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7072267
• 关键词: Morbillivirus; ferrets; host organism interaction; immunosuppression; interferons; measles virus; phosphorylation; polymerase chain reaction; virus infection mechanism; virus protein; virus receptors

DESCRIPTION (provided by applicant): 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.

描述（申请人提供）： 麻疹是一种发现了病毒诱导的免疫抑制现象的疾病：1908 年 von Pirquet 观察到，在急性麻疹病程中，结核菌素皮试反应出现短暂抑制。包括麻疹 (MV)、犬瘟热 (CDV) 和牛瘟在内的麻疹病毒具有免疫抑制作用。这种现象背后的机制很复杂，但病毒受体相互作用可能发挥核心作用：野生型 MV、CDV 和牛瘟病毒株优先使用免疫细胞特异性蛋白 SLAM（分别为人、犬或牛）作为受体。此外，MV 疫苗株 Edmonston 还通过普遍存在的补体激活调节剂、CD46 优先进入细胞，CD46 相互作用改变了对 MV 的免疫反应。此外，MV非结构蛋白V和C引发的进入后宿主控制逃避机制会干扰STAT蛋白磷酸化和干扰素激活。我们将测试两个假设：首先，依赖于 SLAM 的进入对于麻疹病毒的免疫抑制至关重要。其次，V 和 C 蛋白有利于病毒在免疫细胞和全身传播。将使用两种动物模型：用于麻疹的猕猴和用于犬瘟热的雪貂。我们已经选择性地生产了受体盲重组 MV 和 CDV。我们正在构建野生型衍生的 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，并且将鉴定支持 MV 和 CDV 在 PBMC 以及淋巴和非淋巴器官中传播的细胞类型。毒力和免疫抑制将根据分级参数进行表征，包括疾病体征、白细胞数量、病毒血症的强度和持续时间、体外淋巴细胞增殖水平、中和抗体升和细胞因子谱。我们预测在受体识别或进入后水平有缺陷的病毒感染后这些参数会发生差异性变化。结果将在这些预测结果的背景下进行解释。基于感染性 cDNA 的功能测定、测序和回传，将在疾病晚期复制的病毒中寻找恢复毒力的候选突变。这些实验将确定通过特定受体进入细胞的相对重要性以及进入后宿主控制逃避机制对于两个生物学相关的动物系统中麻疹病毒诱导的免疫抑制的相对重要性。