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Inflammatory response and cerebellar abnormalities in MCMV infected newborn mice - potential role of viral immunoevasins

Congenital human cytomegalovirus (HCMV) infection may result in wide spread encephalitis and developmental abnormalities of the CNS. To study the pathogenesis of congenital HCMV infection we have established a model of CNS infection with murine cytomegalovirus (MCMV) in newborn mice. T lymphocytes and NK cells play a central role in control of MCMV infection. However, several proteins encoded by MCMV are devoted to modulate and evade immune control. We postulated that developmental abnormalities and pathohistological lesions in brain of MCMV infected newborn mice can be consequences of either direct viral pathogenesis or inflammatory response toward viral antigens and damaged brain cells. The aim of this study was to identify some parameters associated with MCMV infection of the CNS and potential role of viral immunoevasins that affect the function of CD8+ T lymphocytes and NK cells. Newborn BALB/c mice were infected with either wild type MCMV or virus lacking m152 gene encoding protein that affects expression of NKG2D ligand Rae-1 and presentation of MHC class I molecules. Animals were sacrificed at various days post infection and their brains were processed for immunohistochemistry. Pathohistological lesions associated with infected cells were scattered throughout the brain parenchyma irrespective of the virus used for infection. However, the severity of lesions and the number of infected cells were higher in mice infected with w.t. virus strain. Infected cells were detected in brain tissue during prolonged period, with significant peak at day 11 p.i., whereas in Δ m152- infected mice the peak was absent and productive infection terminated earlier. Significant increase in expression of proinflammatory cytokines and chemokines was observed from day 8th p.i. and followed by infiltration of T lymphocytes. Mice infected with Δ m152 virus showed less T cell infiltration, but the proportion of CD4+ and CD8+ lymphocytes was similar to mice infected with w.t. MCMV. Parallel with inflammatory lesions several developmental abnormalities were observed. The delayed migration of neurons from EGL to IGL, miss-localization and impaired morphology of Purkinje cells were more pronounced in MCMV w.t. infected mice. Altogether, the results show that the intensity of inflammatory lesions and consequent brain pathology correlates with intensity of virus replication in developing brain. Furthermore, the results indicate that viral immunoevasins for NK and CD8+ T cells may play an important role in CMV pathogenesis in CNS.

MCMV; CNS

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