Rie Koide1, Takaya Abe2, Taichi Harimoto1, Anselmo Jiro Kamada3, Yuka Saito1, Matteo Guerrini１, Asami Fujii1, Erica Parrish1, Masayuki Horie4, Hiroshi Kiyonar2, Kazuhiko Yamamoto4, Keizo Tomonaga5, Nicholas F Parrish1
(１．理化学研究所 統合生命医科学研究センター、２．理化学研究所 生命医科学研究センター、３．オックスフォード大学、４．大阪公立大学 大学院獣医学研究科、５．京都大学 医生物学研究所)

Interferon and TLR genes, but not endogenous bornavirus-like elements, limit BoDV1 replication after intracerebral infection

PLoS Pathogens. (2025) 　doi: 10.1371/journal.ppat.1013165

This study genetically dissects the host defense mechanisms against Borna disease virus 1 (BoDV-1), an emerging zoonotic pathogen. Earlier reports proposed that piRNAs transcribed from endogenous bornavirus-like elements (EBLNs) embedded in mammalian genomes might suppress BoDV-1; however, the hypothesis had never been tested directly. We therefore generated (1) IFN-γ receptor–knockout mice, (2) TLR7-knockout mice, and (3) a novel line lacking all piRNA-producing EBLNs, and established a model in which recombinant GFP-expressing BoDV-1 is injected into the lateral ventricles of neonates. Twelve weeks post-infection, BoDV-1 loads in the brain were quantified by RT-qPCR and histology. Viral replication increased significantly in mice lacking either the IFN-γ receptor or TLR7, confirming that these immune pathways are indispensable for BoDV-1 control in the brain. In contrast, complete loss of piRNA-producing EBLNs led only to a transient rise in GFP signal within certain hippocampal regions and did not alter the overall brain viral burden, indicating that EBLN-derived piRNAs exert, at most, a limited antiviral effect under the present experimental conditions. Notably, the inter-individual variability in viral load almost disappeared in TLR7-deficient animals, suggesting that TLR7-dependent responses are a principal determinant of brain infection outcome.
These findings demonstrate that TLR7-mediated immunity is central to the host defense against BoDV-1 and highlight the need for deeper evaluation of the antiviral potential of EBLNs—genomic relics of ancient viral infections. Future work should examine EBLN function in piRNA-rich tissues such as other brain regions and gonads, and test ancestral bornavirus strains that share higher sequence identity with EBLNs to fully elucidate their context-dependent roles.