Tick-borne flaviviruses and type 1 interferons

Flaviviruses comprise a group of arthropod-transmitted pathogens of global medical importance. The most prominent member of the tick-borne flavivirus group is the tick-borne encephalitis virus (TBEV), which is endemic in parts of Europe and Asia and causes several thousand cases of severe neurological illness every year. The pathogenicity of this virus has been the subject of intense investigations, but the knowledge of the mechanisms that cause flavivirus diseases is still far from complete. In recent years much interest has been shown in the involvement of the role of type I interferons (IFNa/ß) in flavivirus infections. However, relatively little is known about the induction of IFNa/ß gene expression and the pathways upstream of the IFNa/ß promoter. Moreover, almost all previous studies apply only to mosquito-borne but not tick borne flaviviruses. We will analyse the role of type I interferons (IFN) in tick-borne encephalitis virus infections. The investigation of mechanisms leading to the induction of IFNa/ß is a prerequisite for understanding pathogenesis. The combination of expertise on TBEV (Prof. Mandl), on IFNs (Prof. Thomas Decker, and on genetic in vivo models (Prof. Müller and Rülicke) provides an ideal background and infrastructure to address for the first time two main issues: First, the molecular mechanisms involved in the production of IFNa/ß after infection with wild type TBEV will be investigated. We will further study the effect of the host IFN system on viral replication in cell culture. Mice deficient in components of the IFN system will be analysed for the specific role of the respective components in the course of infections in vivo. Secondly, we will try to elucidate the role of individual components of the viral life cycle on activation of host cell signalling. For this purpose we will use various viral mutants and subviral reagents for inoculation of cells. The availability of a large pool of viral reagents, which have been established and characterized over decades of research at the Institute of Virology, allows dissection of critical events of the viral replication cycle, including binding to the host cell surface, viral uptake, replication, particle formation and egress. Together these findings will give a detailed insight into the early host response against TBEV infection. Detailed knowledge of the interactions between flaviviruses and the innate immune response is fundamental for a better understanding of the pathogenesis of these disease agents.