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

Subject Area Virology
Term from 2017 to 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 389002253
 
Final Report Year 2024

Final Report Abstract

Ebolaviruses and highly pathogenic arenaviruses constitute some of the most dangerous viruses known to man, often causing severe hemorrhagic fevers with high case fatality rates. Many of them are, therefore, classified as biosafety level 4 (BSL4) viruses, restricting work with infectious viruses to a few high containment facilities worldwide. Given that both ebolaviruses and arenaviruses encode only a relatively small number of proteins, they are highly dependent on proviral host factors, making those excellent targets for indirectly acting antivirals. Unfortunately, our knowledge about their identity, and more importantly about the molecular details of their function in the viral context, which is essential in order to leverage them as targets for antiviral therapies, is limited. To address this issue, we had performed a genome-wide siRNA screen for host factors important for viral RNA synthesis and protein expression of ebolaviruses. The main objectives of this grant were to confirm the importance of top hits from this screen, to characterize them on a molecular level in order to elucidate their precise function in the ebolavirus life cycle, and to then expand these studies to other negative-sense RNA virus families such as arenaviruses and also to study additional host factors involved in related processes. To facilitate this, we used experimental systems called life-cycle modelling systems to dissect the role of host factors in the virus life-cycle, combined with classical virological and molecular biological techniques. As main results we could show that the host factor CAD also in the ebolavirus life cycle fulfils its canonical function as a key component of the de novo pyrimidine synthesis. For NXF1, which is the major nuclear mRNA export factor in host cells, we could identify a novel function, and in a second funding phase we focused mainly on this factor. Specifically, we could show that NXF1 is recruited into viral inclusion bodies, which are cytoplasmic sites of viral RNA synthesis. Here, NXF1 interacts with the nucleoprotein NP, which encapsidates viral RNA, displaces NP from nascent viral mRNA, and then exports this mRNA into the cytoplasm. Using deletion mutants we could further elucidate the molecular details of the interaction between NP and NXF1, resulting in a detailed model for this export mechanism. Interestingly, while we could show that NXF1 (in contrast to CAD) also plays an important role in the life cycle of some arenaviruses, details differ from its role for ebolaviruses, and are the subject of future studies. This work has provided detailed information regarding the function of two host factors in the life cycle of two highly pathogenic virus families, and by doing so provided important information for interfering with these functions in order to combat these viruses.

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