Characterization of the role of the host protein NXF1 in the life cycle of ebolaviruses and other negative-sense RNA viruses

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Ebolaviruses are zoonotic pathogens that cause severe hemorrhagic fevers with high case fatality rates. Until now no approved antiviral therapies are available, and while some experimental treatments show promise in clinical trials, they are antibody-based and thus most likely only active against specific ebolavirus species. Host factors represent a promising target for the development of indirectly active antivirals, since they often are shared between multiple virus species and sometimes even different virus families, so that targetting such host factors allows the development of broad-spectrum antivirals. Further, as these host factors are not encoded by viral genomes, the development of resistances against drugs targetting viral interactions with such host factors is much less likely than when directly targeting the virus. To faciliate such an approach, we have recently investigated the role of three host factors, i.e. NXF1, CAD and UAP56, for the life cycle of ebolaviruses in a DFG-funded project. The most interesting finding from this project was that NXF1 fulfills a novel role in the viral life cycle, and is most likely involved in the export of viral mRNAs from inclusion bodies, which are viral structures in the cytoplasm where virus genome replication and transcription takes place. Further, we could show that this host factor is also important for another negative-sense RNA virus, i.e. Junin virus, which causes severe hemorrhagic fevers in South America. However, currently we do not know whether NXF1 plays the same role in the life cycle of this virus than it does for ebolaviruses. We now propose to continue our studies on NXF1, and to investigate the molecular details of its function for ebolaviruses, in order to define molecular targets for intervention, which allow us to destroy the interaction of NXF1 with ebolaviruses, while preserving its cellular funtion. For this we will map the interaction sites on NXF1 and its viral interaction partner NP, assess which other cellular factors are involved in the process of mRNA export from inclusion bodies, and then analyse the binding dynamics of viral mRNA and the various cellular and viral factors. Further, we want to expand our studies onto Junin virus as a representative for other negative-sense RNA viruses, and assess whether NXF1 might represent a shared host factor and thus a suitable target for the development of broad-spectrum antivirals. For this we will take advantage of the same work flow we have already succesfully used for ebolaviruses, and adapt and apply these methods to Junin virus in order to identify viral interaction partners, and to characterizeing the function of NXF1 for this virus. These studies will provide an important basis for the development of indirectly acting antivirals against ebolaviruses, and potentially also other negative-sense RNA viruses.