Role of N6-methyladenosine in the filovirus life cycle

• Applicant: Dr. Lisa Wendt
• Subject Area: Virology
• Term: Funded in 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 536511667

Filoviruses such as Ebola virus (EBOV) and Marburg virus (MARV) are known to cause severe haemorrhagic fevers in humans. While recent advances led to the development of countermeasures for Ebola virus disease, the case fatality rates remain high and treatment options for diseases caused by other filoviruses like MARV are still extremely limited. Therefore, identifying a host cell pathway that is shared among the human-pathogenic filoviruses could represent a promising target for development of a pan-anti-filoviral therapy. Recently, we could demonstrate that EBOV relies on N6-methyladenosine (m6A) for efficient viral RNA synthesis, but the exact function of m6A methylation in the EBOV life cycle remains elusive. Therefore, the aim of this project is to characterise the function of m6A in EBOV RNA synthesis by identifying which of the host cell proteins that specifically interact with m6A methylated cellular RNA known as m6A reader proteins, mediates the function of m6A in viral RNA species. Furthermore, a combination of different molecular biology methods will reveal the process in EBOV RNA synthesis that is influenced by these m6A reader proteins. The second aim of this project is to assess whether the dependency on m6A methylation is a shared feature among the haemorrhagic fever causing filoviruses by characterising the role of m6A methylation in the MARV life cycle. Since inhibitors of several proteins involved in m6A methylation are currently undergoing clinical trials for a variety of diseases, the third aim of this project is to assess whether any of these inhibitors can be used as anti-filovirus therapy in an animal trial. Identifying new treatment options for the deadly disease caused by several filoviruses will be crucial for containing future outbreaks of the known and potentially also unknown members of the filovirus family.

• DFG Programme: WBP Position