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

波旁病毒属于正粘病毒家族中的霍戈托病毒属。托戈托病毒是从非洲、亚洲和南欧的扁虱中分离出来的，已知会在农场动物中引起严重疾病，但在人类中很少发生。因此，最近从美国一名患有严重发热病并死于多器官衰竭的死亡病例中分离出一种新的ThogotoVirus，命名为Bourbon病毒，这是令人惊讶的。导致这种严重疾病结局的机制尚不清楚，但可能与波旁病毒的意外毒力或宿主先天免疫反应缺陷有关。为了为这些假说提供证据，我们希望在体外和合适的小鼠模型中研究干扰素系统对波旁病毒致病潜力的影响。此外，我们想要确定解释这种新出现的ThogotoVirus对干扰素敏感性的分子决定因素。与其他ThogotoVirus不同，在小鼠身上的初步分析显示，波旁病毒对干扰素的抗病毒作用具有出人意料的高敏感性。因此，我们假设波旁病毒缺乏通常控制干扰素系统的抗病毒作用的毒力因子。通过在细胞培养和小鼠模型中直接比较波旁病毒与其他霍戈托病毒分离株的干扰素诱导和致病潜力，以及通过分析具有潜在病毒基因产物缺陷的重组病毒，我们计划确定毒力因素，包括可能的干扰素拮抗剂，这是导致霍戈托病毒高毒力的原因。最后，我们计划评估应对未来人畜共患波旁病毒传播的治疗方案。

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.