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Delayed cerebellar development and altered chemokine expression in the CNS as a result of peripheral murine cytomegalovirus infection of neonatal BALB/c mice

Human Cytomegalovirus (HCMV) infection of the developing CNS results in encephalitis and disordered neuronal migration. Similar pathological manifestations in the CNS, specifically in the cerebellum, are also observed following murine cytomegalovirus (MCMV) infection of neonatal mice. However, the pathogenic mechanisms leading to MCMV and HCMV induced CNS maldevelopment remain undefined. Since neuronal migration and foliation are ongoing in the cerebellum until postnatal day 21, we investigated if peripheral MCMV infection of newborn mice affected postnatal cerebellar development. In this mouse model, newborn Balb/c mice were intra-peritoneally infected with a low titer of MCMV. At 5 days post-infection (dpi) MCMV was detected in the brain parenchyma by using immunohistochemistry, PCR and plaque assays. Infectious virus peaked at 12 dpi but was undetectable by 16 dpi ; however, MCMV genomic DNA was still shown to be present by PCR at 21 dpi. Peripheral infection resulted in delayed cerebellar morphogenesis. Early in infection (P8-P16), cerebellum from MCMV infected mice displayed significantly less foliation than mock infected mice. In addition, the external granular layer (EGL) was increased in thickness suggesting delayed granule neuron migration in infected mice. Both EGL thickness and foliation however, were more comparable to mock infected controls at later time points (P18-21). Since chemokines play a crucial role in neural development and in host immune response to viral infection by recruitment of immune effector cells, we examined the pattern of chemokine expression in the CNS after peripheral MCMV infection of newborn mice. By using Ribonuclease Protection Assays (RPA) we demonstrated that RANTES, MCP-1, IP10 and TCA-3 are the major chemokines expressed in the CNS starting at 8 dpi. MIP1-alpha and MIP1-beta were also present however at lower levels. Chemokine expression levels peaked at 14 dpi and decreased at later time points. However at 21 dpi, RANTES expression was still significantly high compared to MCP-1, IP-10 and TCA-3. Since our results show that the increase in chemokine expression levels correlated with a decrease in viral titer and with delayed cerebellar morphogenesis, these findings suggest that host chemokine expression was associated with MCMV clearance in the CNS, however it may also have an adverse effect on cerebellar development

CNS; MCMV

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