Arenaviruses such as Lassa Fever Virus (LASV) can cause hemorrhagic fevers in humans and can potentially be employed as biological agents. The necessity of high-level containment restriction to work with this virus (in BLS-4 Laboratory) and the costly expenses of using non-human primates for LASV studies significantly hinder progress in understanding the disease pathogenesis. Guinea pig infected by a related arenavirus Pichinde (PICV) represents a safe, convenient, and economical small animal model for Lassa fever. A spleen-passaged PICV causes Lassa fever-like symptoms that are limited to guinea pigs. As with human LASV infection, PICV viremia levels are closely associated with disease outcome and can accurately predict lethality in guinea pigs. Additionally, PICV-infected guinea pigs exhibit vascular leakage syndrome and viral distribution similar to individuals infected by LASV. We have developed for the first time molecular clones for both virulent (P18) and avirulent (P2) strains of PIVC and have identified genetic changes between the strains that may be responsible for the deadly pathogenic nature of the virus in infected animals. To determine the viral virulence factor(s), we propose to generate recombinant viruses using our recently developed reverse genetics system and to assess their effects on pathogenicity in guinea pigs.These studies will provide important insights into the molecular mechanisms of virally induced hemorrhagic fevers, which may lead to the development of effective treatment modalities and vaccines against serious and sometime fatal hermorrhagic virus infections.
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