MOLECULAR BASIS OF ARENAVIRUS VIRULENCE

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DESCRIPTION (Adapted from Applicant's Abstract): Dr. Salvato states that arenaviruses are important pathogens in man and are transmitted from wild rodent carriers. Most studies in this area utilize the prototype arenavirus, lymphocytic choriomeningitis virus (LCMV), to explore the host/response to infection and the mechanisms of viral pathogenesis. Completion of the LCMV sequence by Dr. Salvato facilitates studies of the virus structure, regulatory mechanisms, and virulence determinants. The current goal is to expand these studies to include the most virulent virus in the group, the Lassa Fever Virus. Study of Lassa Fever Virus is complicated by its geographic restriction to Western Africa and the need to use Level 4 containment precautions. The studies will combine molecular biology and animal models to obtain a better knowledge of Lassa Fever Virus structure, the host immune response infection, and viral determinants of virulence. The specific themes are 1. to complete the genomic sequence analysis of Lassa Fever Virus, 2. to do a molecular characterization of Lassa Fever Virus infection by examining Lassa gene expression, antigenemia, and antibody and cellular immune responses to specific Lassa Fever Virus gene products in the blood of infected humans and in the guinea pig model, and 3. to develop an oral vaccine for Lassa Fever Virus using the guinea pig model system and salmonella typhimurium vectors. The comprehensive approach to understanding the biology of Lassa Fever Virus will establish rational goals for the design of protective vaccines. Crucial information will derive from the studies of human beings that survive natural infection and guinea pigs that survive experimental oral inoculation of Lassa Fever Virus. These experiments with virus will be performed in Level 4 containment facilities at the CDC in Atlanta. Reagents generated in consequence of their analysis of Lassa Fever Virus sequence will provide new means for evaluating virus replication and host responses in these two systems. Based on these studies and the consideration that the natural route of infection is likely to be oral, the investigator has decided to initiate vaccine studies by generating live attenuated recombinant Salmonella typhimurium strains that express Lassa Fever Virus proteins. This form of oral vaccine should induce mucosal immunity to virus and may be protective. Vaccine efficacy will be tested in the guinea pig model system. Lassa Fever Virus is an important pathogen in West Africa and an emerging pathogen for the rest of the world.These studies will significantly enhance understanding of this highly virulent agent and will attempt to provide an inexpensive oral vaccine.