Murine retroviral-induced spongiform neuronal degeneration parallels resident microglial cell infection: ultrastructural findings

Abstract

Ts1 Moloney murine leukemia virus (MoMuLV) is a neurovirulent retrovirus that causes a progressive, noninflammatory, spongiform, neurodegenerative disease in mice. The temporal localization of cellular targets for virus replication and the genesis of ultrastructural spongiform changes in the central nervous system (CNS) of CFW/D mice inoculated at birth with neurovirulent ts1 MoMuLV and nonneurovirulent wild type (wt) MoMuLV were studied comparatively by transmission electron microscopy. Cellular targets for both ts1 and wt MoMuLV infection were sequentially (a) splenic megakaryocytes, (b) CNS intravascular platelets and capillary endothelia, and (c) resident CNS pericytes and microglia. When compared with wt MoMuLV-infected mice, ts1 MoMuLV-infected mice had amplified localization of virus to microglia with disease progression that paralleled the development of spongiform changes both temporally and spatially. Virus infection of neurons was never observed. Spongiform lesions originated from the dilated cytocavitary system of proximal neuronal processes (predominantly dendrites) and from vacuolated myelin sheaths of distal axons. As the disease progressed, the severity of the spongiform lesions in ts1 MoMuLV-infected mice increased rapidly and was associated with increased number of virions and virus-infected cells. Lesions in wt MoMuLV-infected mice were not severe and regressed terminally with apparent clearance of virus from the CNS. These studies indicated that murine retroviral-induced spongiform lesions originated from both neuronal and oligodendroglial degeneration; splenic megakaryocytes, platelets, and cell-free viremia contributed to systemic dissemination of virus to the CNS; microglia were the major cell target and reservoir for virus infection in the CNS; and the neurovirulence of ts1 MoMuLV occurred by enhanced replication rather than by a fundamental change in cellular tropism. The identification of microglia as the major CNS cell target for virus infection and the absence of productive virus infection of neurons suggested an indirect mechanism for murine retroviral-induced neuronal dysfunction.