Progressive Neuroinvasive and Neurodegenerative Disease Due to Potosi Virus in an Immunosuppressed Adult

<title>Abstract</title> <p>Potosi virus (POTV), an orthobunyavirus first isolated in 1989, has been detected in multiple mosquito species across the United States, but its pathogenic potential in humans remains uncertain. Here we report the first in-depth pathological and pathogenetic characterization of POTV central nervous system (CNS) infection manifesting as rapidly progressive dementia in a woman receiving long-term rituximab therapy. Antemortem metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid detected POTV in the setting of progressive brain volume loss on longitudinal neuroimaging, culminating in death almost a year after symptom onset. Comprehensive postmortem neuropathological examination demonstrated diffuse meningoencephalitis with widespread spongiform neurodegeneration and evidence of POTV infection throughout all evaluated CNS subregions (n = 75), with detectable viral replication in 80% of subregions. Quantitative spatial and machine learning–based analyses demonstrated marked regional heterogeneity in viral burden, with the highest genomic POTV RNA levels in the cerebellum (p &lt; 0.0001), where viral RNA density correlated with spongiosis and severe Purkinje and granule cell loss (ρ up to 0.39; p &lt; 0.001). Hierarchical clustering identified distinct CNS compartments characterized by chronic infection and progressive neurodegeneration, while comparative sequencing demonstrated intrahost viral variation with region-specific mutations. Collectively, these findings demonstrate that POTV can cause persistent CNS infection associated with progressive neurodegeneration in B-cell–depleted hosts, raising the possibility that chronic viral infection may underlie a subset of transmissible dementia-like syndromes and highlighting the need to consider emerging arboviruses in unexplained neurodegenerative disease.</p>