Investigations into the viral molecular determinants of lethality of Punta Toro virus (Bunyaviridae, phlebovirus) in the Syrian hamster.



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Punta Toro virus (PTV) is transmitted by sandlfies (Lutzomyia spp.) in Panama and Northern Columbia and causes an acute febrile illness in humans lasting 2-5 days. Human seroprevalence in regions within Panama have been reported up to 34% in the most easterly region of Darien however little is understood about the clinical spectrum of PTV induced illness, pathogenic mechanism and the viral ecology with respect to animal reservoirs and distribution. This dissertation addresses questions regarding viral genetics and their affect on virulence in the hamster model of Phlebovirus pathogenesis. This study reports that PTV strains isolated west of the Panama Canal are not lethal in hamsters and phylogenetic analysis of the coding sequences reveals the presence of genetic clades, indicating that PTV strains occupy distinct ecological niches within Panama. Studies reported here also reflect the absence of naturally occurring viral reassortants and in vitro reassortment experiments demonstrate segment segregation preferences amongst the RNA segments during replication and/or packaging. Viral reassortants were utilized to investigate the viral genome segment(s) responsible for hamster lethality, this study finds that the S segment can confer lethality independently. Further genetic investigation reveals that the NSs gene encoded by the S segment is a type 1 interferon antagonist. Taken together, this evidence indicates a mechanism of pathogenesis whereby early innate immune suppression by the viral NSs gene/protein in infected cells leads to uncontrolled viral replication that ultimately results in hamster death.



reassortants, Punta Toro virus, phlebovirus, Interferon antagonism, hamster lethality