Study uncovers key structure in fatal Borna disease virus 1

Cases of Borna disease virus 1, or BoDV-1, are extremely rare in humans, but in those who develop disease the outcome is severe, almost always resulting in fatal encephalitis or inflammation in the brain. This zoonotic virus belongs to the order Mononegavirales, which includes the lethal viruses responsible for Ebola virus disease, measles, and rabies.

The nucleoprotein-RNA complex in these viruses protects its genomic RNA and supports viral RNA synthesis, so understanding the structure of this complex is essential to targeting viral replication. Structural characterization has been completed for several mononegavirus families that more commonly infect humans, but detailed information for the family Bornaviridae has not been sufficiently explored.

After their previous structural work on Ebola virus nucleoprotein-RNA complexes, a team of researchers from Kyoto University, Osaka Dental University, and Osaka Metropolitan University recognized this key unresolved question and collaborated to address it.

Bornaviruses are less well known than many other human RNA viruses, yet they represent the last major unresolved case for nucleoprotein-RNA structural analysis among human-infecting mononegaviruses. Closing this long-standing gap and connecting structural biology with virological function were major motivations for our team."

Yukihiko Sugita, first author

Using cryo-electron microscopy, the researchers obtained high-resolution images of BoDV-1 nucleoprotein-RNA complexes and performed computational classification to separate and reconstruct the distinct assembly states of each complex in the sample. They then used mutational and functional assays to test nucleoprotein-RNA residues and evaluate their roles in viral RNA synthesis and assembly.

The results provided the team with the first detailed structural description of the nucleoprotein-RNA complex in the family Bornaviridae. Their observations revealed the three-dimensional structure of this nucleoprotein-RNA complex, showing ring-like assemblies and viral RNA binds in the inner groove. They also found that each nucleoprotein subunit accommodates eight RNA nucleotides, suggesting a binding mode distinct from those reported for other related viruses.

The researchers were surprised to observe that mutations impairing RNA binding disrupt viral RNA synthesis, but that nucleoprotein assemblies can form even without RNA. Together, these findings suggest an incremental model in which nucleoprotein assembly and RNA engagement are separate but coordinated processes.

This study provides a molecular framework for a systematic comparison of Bornaviridae nucleoprotein-RNA architecture alongside that of other mononegaviruses, and supports broader questions about the principles governing nucleoprotein-RNA interactions. It also lays the groundwork for future antiviral studies targeting viral replication through nucleoprotein-RNA interactions.

Next, the team would like to analyze complexes derived from infected cells as well as those with longer RNA segments. They also plan to integrate structural analysis and biochemical approaches in order to observe intermediate complex formation states and compare them with those of related viruses.