MECHANISMS OF VIRAL PATHOGENESIS

病毒性疾病的发病机制和流行病学， 嗜神经性或非嗜神经性，都受到遗传因素的影响， 病毒和宿主 我们的研究涉及生物学和 这些宿主因子之一Mx的分子表征 该系统专门针对流感病毒。 从最初的观察开始， 近交系在实验性流感中自发存活 感染，一个基因存在两种等位基因形式，Mx+和Mx- 发现控制感染过程：Mx+的存在 与流感耐药性相关，而Mx-与 流感易感性 在Mx+细胞中，而不是在Mx-细胞中， 干扰素诱导一种独特的蛋白质，Mx蛋白。 这种蛋白质， 当通过重组DNA技术在大肠杆菌中组成型表达时， MX细胞，赋予针对流感病毒的特异性保护 文化感染。 我们的研究重点是Mx的结构/功能关系 Mx蛋白作用机制、分布 和功能的Mx系统在动物王国，并在 转基因方法将流感抗性转移到Mx- 动物 我们已经表明，一个独特的Mx抗体，当 微注射到细胞中，抑制了正常的积累， 小鼠Mx蛋白在细胞核中，并特异性中和 其抗病毒活性。 小鼠Mx上的核转运信号 蛋白质也已被鉴定，其缺失已被证明 降低，但不是消除，蛋白质的抗流感活性。 的 小鼠Mx蛋白已在昆虫细胞中表达， 确定重组蛋白具有活性。 我们还表明 Mx基因至少与另外一个物种老鼠 以流感特异性方式起作用， 可以这 最后，我们已经产生了四只Mx转基因动物， 目前正在分析Mx蛋白的表达， 各种组织和体内抗病毒耐药性。

Pathogenesis and epidemiology of viral diseases, be they neurotropic or not, are influenced by genetic factors specified by both virus and host. Our studies deal with the biological and molecular characterization of one of these host factors, the Mx system, which is operative specifically against influenza viruses. Starting with the original observation that mice of one particular inbred strain spontaneously survive experimental influenza infection, a single gene existing in two allelic forms, Mx+ and Mx- was found to control the course of infection: the presence of Mx+ is correlated with influenza resistance, and that of Mx-with influenza susceptibility. In Mx+ cells, but not Mx- cells, interferon induces a unique protein, the Mx protein. This protein, when constitutively expressed by recombinant DNA techniques in Mx-cells, confers specific protection against influenza virus infection in culture. Our studies focus on the structure/function relationship of the Mx protein, on the mechanism of Mx protein action, on distribution and function of the Mx system in the animal kingdom, and on the transgenic approach to transfer influenza resistance to Mx- animals. We have shown that a distinct Mx antibody, when microinjected into cells, inhibits the normal accumulation of the mouse Mx protein in the cell nucleus and specifically neutralizes its antiviral activity. A nuclear transport signal on the mouse Mx protein has also been identified and its absence has been shown to reduce, but not abolish, the protein's anti-influenza activity. The mouse Mx protein has been expressed in insect cells and the recombinant protein determined to be active. We have also shown that the Mx cognates of at least one additional species, the rat, act in an influenza specific way much as the mouse Mx protein does. Finally, we have produced four Mx transgenic animals which are currently being analyzed for expression of Mx protein in various tissues and for antiviral resistance in vivo.