Influence of the interferon system to control tick-transmitted Bourbon virus

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Bourbon virus belongs to the Thogotovirus genus within the family of orthomyxoviruses. Thogotoviruses were isolated from ticks in Africa, Asia and South Europe and are known to cause severe diseases in farm animals but only rarely in humans. Therefore, the recent isolation of a new Thogotovirus, designated Bourbon virus, from a fatal case in the USA, who suffered from a severe febrile disease and died from multi organ failure, was surprising. The mechanisms that caused this severe disease outcome is unknown but potentially linked to an unexpected virulence of the Bourbon virus or defects in the host innate immune response.To provide evidence for these hypotheses we want to study the impact of the interferon system on the pathogenic potential of Bourbon virus in vitro and in a suitable mouse model. Moreover, we want to identify molecular determinants explaining the interferon sensitivity of this newly emerging Thogotovirus. In contrast to other Thogotoviruses, preliminary analyses in mice revealed an unexpected high sensitivity of Bourbon virus to the antiviral effects of interferon. We therefore hypothesize that Bourbon virus lacks a virulence factor that normally controls the antiviral action of the interferon system. By directly comparing the interferon induction and pathogenic potential of Bourbon virus with other Thogotovirus isolates in cell culture and in the mouse model and by analysing recombinant viruses with defects in potential viral gene products, we plan to identify virulence factors including possible interferon-antagonists that account for the high virulence of Thogotoviruses. Finally, we plan to evaluate therapeutic options to respond to future zoonotic transmissions of Bourbon virus.