Abstract
Human cytomegalovirus (HCMV) can frequently infect the central nervous system (CNS) in the setting of immunosuppression such as translantation and infection with the human immunodeficiency virus (HIV). Our laboratory previously reported that HCMV infection of human brain aggregates preferentially infected a mikcroglial/macrophage (M/M) and caused a neuropathology that differed between strains and could occur in the absence of antigen expression. We extended these studies by infecting a human brain cell aggregate model with four low passage clinical isolates of HCMV. Two patterns of cytopathology emerged after infection; a lacy eosinophilic appearance or a glial nodular formation concomitant with a decreased aggregate size. None of the infections were positive for HCMV antigen; however, all were positive for HCMV DNA. We also infected primary macrophages and microglial cells with the same HCMV isolates. Microglial cells were more susceptible to HCMV infection resulting in a lytic infection. Production of potentially neurotoxic cytokines, IL-1, IL-6 and TNFα, from HCMV-infected macrophages and microglial cells were evaluated to explain brain aggregate cytopathology. Supernatants from HCMV-infected macrophages and microglial cells produced similar levels of TNFα (> 30 pg ml−1) but showed strain and cell source variation in the production of IL-6; microglial cultures produced < 4 fold higher levels. None of the supernatants contained IL-1. Treatment of brain aggregates with either IL-6 or TNFα resulted in morphologic alterations and/or decrease in size consistent with HCMV infection or supernatant treatment.
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