Insights on the adaptation of Sudan virus in guinea pigs and its implications in viral pathogenesis

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Emeterio, Karla
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Sudan virus (SUDV) is a filovirus that belongs to the genus Ebolavirus. SUDV has been associated with several human cases of severe viral hemorrhagic fever in Sudan and Uganda. The average case fatality rate is about 50%. However, there are no licensed therapies or prophylactics for the treatment of SUDV disease. Initial evaluations of the effectiveness of new filovirus countermeasures are done in small rodent animals such as mice, hamsters, and guinea pigs. However, filoviruses are apathogenic in immunocompetent rodents, thus necessitating virus adaptation through serial passaging in the host. The virus acquires genomic mutations that lead to increased virulence and lethality during this process. In 2015, the first and only rodent animal model for SUDV was developed in guinea pigs. The repeated passaging of SUDV in the animal resulted in a uniformly lethal SUDV with 16 mutations of unknown significance. Here we show the timeline of mutation appearance during the adaptation process and at what frequencies they occurred by utilizing an amplicon-based high throughput sequencing approach. It was found that the viral genome acquired multiple transient mutations during the adaptation process, only 18 of which were retained in the guinea pig adapted SUDV. Most of these mutations were at a 99% frequency by passage 17. Three of the adaptive mutations were also already present in the starting virus and increased in frequency over time. Unique to this study was the identification of a novel mutation in the VP40 gene that existed early in the series and was selected for by the virus as passaging progressed. The roles that these 18 adaptive mutations play in the pathogenesis of SUDV may be related to viral replication and/or immune evasion. Overall, this study highlights hotspots within the viral genome that might be important in conferring increased virulence phenotype in the guinea pig host.
Sudan virus, Next generation sequencing, Adaptation, Guinea pig animal model, Filovirus, Serial passaging, Deep sequencing, Mutations, Ebolaviruses