MECHANISMS OF VIRAL PATHOGENESIS

病毒性疾病的发病机制和流行病学

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.