Multimodal profiling of immune responses reveals innate-adaptive immune imbalance in human bornavirus encephalitis.

Human bornavirus encephalitis (BVE) is a rare, emerging and fatal zoonotic disease mainly caused by the Borna disease virus 1 (BoDV-1), a non-cytolytic RNA virus. Despite increasing recognition, the immunopathogenesis of human BoDV-1 infection remains insufficiently characterised. Complete coronal and sagittal brain sections from four fatal BoDV-1 cases were analysed using digitised immunohistochemistry to quantify viral distribution and tissue responses. Transcriptome-based analyses characterised local immune cell profiles in relation to viral loads measured by RT-qPCR. BoDV-1 viral loads varied substantially between cases but showed region-specific enrichment in the basal ganglia and hippocampus, correlating with lymphocyte presence and reactive microglia and astrocytes. Immune cell deconvolution revealed viral load-dependent modulation dominated by innate immune and glial populations, including metabolic and reactive astrocyte states, IFNγ-responsive microglia, and dendritic cells, macrophages, neutrophils, basophils, and CD8⁺ T cells. This was accompanied by induction of interferon-stimulated genes, antigen presentation, protein synthesis, and oxidative stress pathways, with a transcriptional signature resembling non-lytic viral and autoimmune-like neuroinflammatory conditions rather than lytic infections. These findings support a model of BoDV-1 encephalitis characterised by a prominent innate immune response and comparatively limited adaptive immune signatures. This imbalance might potentially contribute to impaired viral clearance and extensive tissue damage, a possible relationship that warrants further investigation.