Virus-host interactions essential for genome replication and transcription of Lassa virus

• Applicants: Dr. Jan Kosinski, Ph.D.; Dr. Maria Rosenthal
• Subject Area: Virology ; Bioinformatics and Theoretical Biology ; Structural Biology
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 436508883

Lassa virus, the causative agent of potentially fatal Lassa fever, belongs to the family of Arenaviridae, which are negative strand RNA viruses with a segmented genome. The virus is mainly endemic in West Africa, where annual outbreaks have devastating consequences to the society and economy. Lassa virus is listed on the WHO R&D Blueprint, which urges to focus R&D on under-researched pathogens with epidemic potential, for which there are no, or insufficient countermeasures available. Therefore, the development of medical countermeasures, including broad-spectrum antiviral drugs, is a research priority. However, our knowledge on the viral and cellular components critically involved in the replication of these viruses is very limited. Viruses interact with the host to use the cellular metabolism for amplification. Protein-protein interactions can be promising targets for the development of antiviral drugs. A key component in the lifecycle of these viruses is the viral L protein, a large multi-domain protein containing the RNA-dependent RNA polymerase. As data on the L protein is scarce, we aim at studying the interactions of the L protein with the host cell combining different screening approaches, advanced bioinformatics as well as biochemical and structural biology methods. The screening for cellular interaction partners using recombinant viruses and haploid genetic screens is presented as preliminary data. The specific objectives of the proposal include (1) final screening experiments to then (2) select targets by bioinformatic systems analysis. Furthermore, (3) we will purify selected cellular proteins for functional analyses and (4) map the specific interaction sites using structural biology techniques. We will (5) develop bioinformatic tools to finally (6) construct mechanistic models of virus-host interactions. In summary, we will provide an integrated view of the essential interactions of the L protein with cellular proteins to provide a basis for future drug design.

• DFG Programme: Research Grants