Identifying Macrophages as Peripheral Transporters of JC Polyomavirus 2258486

Abstract Introduction JC polyomavirus (JCPyV) is a DNA virus that can cause progressive multifocal leukoencephalopathy (PML) upon reactivation. PML is a rare but often fatal demyelinating disease of the central nervous system (CNS) characterized by motor dysfunction, speech impairment, and seizures. Currently, there is no cure, but treatment relies on boosting host immune responses. JCPyV typically establishes a benign infection in the kidney tubule epithelium. Viral reactivation may occur under severe immunosuppression such as radiation, HIV infection, organ transplantation, or immunosuppressive drug therapy. While JCPyV infection of astrocytes and oligodendrocytes is well established, mechanisms of viral entry into the CNS remain unclear. Macrophages are key candidates as peripheral immune cells capable of trafficking JCPyV to the CNS. We hypothesize that monocytes and macrophages are targets of JCPyV infection and may elucidate how the virus travels from the kidney to the CNS. Methods Human monocytes were isolated from healthy donor peripheral blood mononuclear cells (PBMCs) using CD14+ bead isolation and differentiated into macrophages with human M-CSF in vitro. Digital polymerase chain reaction (dPCR) was performed to verify JCPyV infection in monocytes and macrophages. Fixed and sectioned PML patient brain tissues were stained by immunohistochemistry to assess macrophage infection in vivo. Results Preliminary dPCR data reveal JCPyV infection of both monocytes and macrophages ex vivo, with robust detection of two distinct viral probes. PML brain tissue also showed JCPyV-positive macrophages; however, further studies are needed to determine whether these cells migrated from the periphery or are brain resident. Conclusion These findings suggest that human monocytes and macrophages can support JCPyV infection and may act as cellular vehicles for viral dissemination to the CNS. Understanding macrophage-mediated viral transport could provide key insights into PML pathogenesis and identify new therapeutic targets. Funding Source R01NS116278 Topic Categories Viral Immunology (VIR)