MEASLES VIRUS STUDIES IN A TRANSGENIC MODEL

麻疹病毒在中国造成严重的发病率和死亡率 人类人口。尽管减毒疫苗取得了成功，但麻疹 每年仍有100多万儿童死于这种病毒。问题 因为疫苗对在此之前感染的儿童无效 他们九个月大的时候。人们认为这是因为 母源抗体和/或病毒诱导的免疫抑制或其他 接种疫苗后的后遗症。此外，麻疹还会引起 超急性变态反应性疾病和慢性持续性(亚急性 硬化性全脑炎)神经元紊乱。然而，我们的 对麻疹分子特征的认识和认识 病毒，对两者的免疫和免疫病理反应 感染和疫苗接种以及病毒如何在神经元中持续存在是 人们对此知之甚少。 为了解麻疹病毒感染的发病机制 并确定免疫保护性反应，包括B和T 细胞表位，我们将开发和利用一种新型的小动物 模特。我们和我们的同事已经确定了可能的受体 对于麻疹病毒，膜辅因子蛋白(MCP，CD46)。 麻疹病毒对人和猿类是允许的，但对小鼠不是 细胞。然而，小鼠MC57和3T3细胞几乎不允许 麻疹病毒在以下情况下变得允许并产生后代病毒 稳定表达四种CD46亚型中的任何一种，尽管亚型 Bc1和bc2与较高程度的合胞体有关 队形。我们建议在小鼠体内表达CD46的c DNA。 自身，一种β肌动蛋白(通用)和细胞特异性(神经元特异性 烯醇化酶，RIP)启动子。这将允许我们生成一个 转基因麻疹病毒模型在一个小的，廉价的， 基因可操控的宿主，小鼠，其免疫学 回应(S)很容易被操纵。 表达麻疹病毒受体的转基因小鼠将被 有助于研究麻疹病毒的致病机理，包括毒力， 组织嗜性，在存在或存在的情况下引发免疫反应 缺乏过继转移的抗体，用于定位人类人类白细胞抗原 利用双转基因小鼠表达限制性CTL表位 CD46和人类白细胞抗原I类分子，创建亚单位疫苗和 对新开发的疫苗进行测试。

Measles virus causes significant morbidity and mortality in the human population. Despite a successful attenuated vaccine, measles virus still kills over one million children a year. The problem being that the vaccine is inefficient in children infected prior to their ninth month of age. This is believed due to the presence of maternal antibody and/or virus induced immunosuppression or other late effects following vaccination. Further, measles causes a hyperacute allergic disease and a chronic persistent (subacute sclerosing panencephalitis) neuronal disorder. Yet our understanding and knowledge of the molecular features of measles virus, the immunologic and immunopathologic responses to both infection and vaccination and how the virus persists in neurons are poorly understood. In order to understand the pathogenesis of measles virus infection and to identify the immune protective response, including B and T cell epitopes, we will develop and exploit a novel small animal model. We and our colleagues have identified the putative receptor for measles virus, the membrane cofactor protein (MCP, CD46). Measles virus is permissive for human and simian but not murine cells. However, murine MC57 and 3T3 cells barely permissive to measles virus become permissive and produce progeny virus when stably expressing any of the four CD46 isoforms, although isoform BC1 and BC2 are associated with a higher degree of syncytial formation. We propose expressing the cDNA of CD46 in mice under its own, a beta actin (universal) and cell-specific (neuron specific enolase, RIP) promoters. This will allow us to generate a transgenic model of measles virus in a small, inexpensive, genetically manipulable host, the mouse, whose immunologic response(s) can be easily manipulated. Transgenic mice expressing the measles virus receptor will be useful for studying measles virus pathogenesis including virulence, tissue tropism, eliciting immune responses in the presence or absence of adoptively transferred antibodies, for mapping human HLA restricted CTL epitopes using double transgenic mice expressing CD46 and HLA class I molecules, creating a subunit vaccine and for testing of newly developed vaccines.