Full-length genomic sequencing and characterization of Borna disease virus 1 isolates: Lessons in epidemiology

Borna disease virus 1 (BoDV-1) is a nonsegmented, negative-strand RNA virus that infects mammals including humans. BoDV-1 strains occur globally, dominate the species Mammalian 1 bornavirus, and display highly conserved genomes and persistent infection (brain, blood). Subclinical infections prevail but the rare fatal outcomes even in people need awareness and risk assessment. Although BoDV-1 strains were successfully isolated, only limited full genomic sequences are available. In this study, the entire genomes of two natural BoDV-1 isolates (Hu-H2, Equ-Cres) and one vaccine strain (DessVac) were sequenced. They were compared with 20 genomes and 20 single-gene sequences (N and P) of worldwide human strains from psychiatric and neurologic patients and animal strains from horses with Borna disease available at GenBank. Phylogenetic analyses confirmed a low divergence not exceeding 5.55%, 5.34%, and 4.94% at the genome, P-gene, and N-gene level, respectively, characteristic of BoDV-1. Human viruses tended to cluster at the country level but appeared to be independent of hosts' diseases and/or time of isolation. Notably, our data also indicated that human viruses provided individual genetic signatures but exhibited no distinct genotypes that separated them from animal strains. Sequence similarities thus occurred between different host species and distant geographic regions, supporting global BoDV-1 prevalence. Overall low genetic divergence among BoDV-1 viruses shown here also argued against zoonotic concepts, requiring further clarification beyond sequence similarities. Finally, unlike shared sequence conservation, phenotyping of natural and laboratory variants revealed that they manipulated host cells differently, underpinning the authenticity of the human BoDV-1 strains.