Molecular basis of adaptation of Borna disease virus to a new host species

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Borna disease virus (BDV), a negative-strand RNA virus that induces neurological disease in farm animals, can be adapted to replicate in the brain of rodents. Little is known about the critical molecular events of virus adaptation to new animal hosts. Recent results from our laboratory showed that BDV recovered from cloned cDNA can efficiently grow in rat brain, but surprisingly not in mouse brain. After a single passage in rats, a virus variant emerged that readily grew in mice. The variant possessed a total of five amino acid changes from the parent. The changes were located in the polymerase components N, P and L. These observations led to the working hypothesis that, in rodents, the host range of BDV is primarily determined by the activity profile of the viral polymerase rather than by viral surface molecules. In the proposed research project we plan to use reverse genetics technology to explore the relative contributions of the various BDV polymerase mutations in host range restriction. We further propose a series of experiments aimed at elucidating the molecular basis of the host restriction that appears to be a direct consequence of altered viral polymerase activity. The project will provide a technology for the generation of recombinant viruses necessary to elucidate the molecular basis of viral pathogenesis in the mouse model system of Borna disease. Second, it will yield new biological insights into an intracellular restriction mechanism that determines the host range of a neurotropic virus.