Grant: Operating Grant - PA: Regional Partnership Program : Manitoba

Rabies is a serious problem in Canadian wildlife and it is an important public health problem in developing countries. Human rabies is almost invariably fatal. An understanding of how rabies virus causes disease will be helpful in developing new strategies for the prevention and treatment of rabies and potentially also other viral and neurologic diseases. There is promising recent data from the laboratory of the principal applicant and others that rabies virus causes disease by injuring processes of neurons, including axons and dendrites. This damage is not apparent on routine pathological studies. The applicants have recently demonstrated that the infection likely causes damage by oxidative stress, which involves injury to tissues caused via by-products of the metabolism of oxygen called reactive oxygen species. Oxidative stress is important in a variety of human neurological diseases, including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, and also in experimental infection of the brain in mice produced by herpes simplex virus. Using studies on cultured sensory nerve cells the mechanisms will be determined by which rabies virus infection produces oxidative damage to neuronal processes. In particular, the role of mitochondria and a variety of key regulatory molecules will be evaluated using techniques that include imaging of live nerve cells and gene silencing technology. This work will give important insights into how rabies virus causes disease of the nervous system. This information will be important in the development of new therapies for patients with rabies and other viral diseases and also be applicable to a variety of other virological and neurological diseases.