Structural basis of Nipah virus genome replication and transcription

• Applicant: Professor Dr. Hauke Sven Hillen
• Subject Area: Structural Biology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 582178838

Nipah virus (NiV) is an emerging zoonotic pathogen belonging to the Mononegavirales order. With fatality rates reaching up to 85%, NiV poses a severe threat to public health and is listed by the World Health Organization as a priority pathogen with epidemic potential. As a non-segmented negative-strand RNA virus (nsNSV), NiV relies on its RNA-dependent RNA polymerase (RdRp) for both genome replication and gene transcription, processes essential for viral propagation and pathogenesis. The NiV RdRp complex is comprised of the L protein, which contains all catalytic activities required for de novo RNA synthesis and 5′ capping, as well as its cofactor, the P protein. However, the detailed molecular mechanisms of genome replication and transcription by NiV and other nsNSVs remain unknown. We have recently reported structures of the NiV L-P complex in the apo and an early elongation state, which provided the first high-resolution insights into RNA synthesis by an nsNSV RdRp and revealed conformational rearrangements upon nucleic acid binding. Building on this, we here propose to define the molecular mechanisms underlying RNA elongation and co-transcriptional capping by the NiV polymerase and investigate the molecular principles governing higher-order formation of functional polymerase assemblies, a feature that likely plays a key role in coordinating genome replication and transcription in vivo. Specifically, we will reconstitute defined elongation and co-transcriptional capping intermediates in vitro, determine their structures using high-resolution single-particle cryo-EM and characterize them functionally in vitro and in cellulo (Objective 1). Furthermore, we will investigate the role of the N protein in NiV genome replication and transcription and determine the molecular basis for the formation of higher-order viral polymerase assemblies (Objective 2). Taken together, this project will provide a detailed mechanistic picture of nsNSV RNA synthesis and maturation and may provide a framework for the development of novel antiviral compounds.

• DFG Programme: Research Grants