A variant of lactate dehydrogenase-elevating virus, designated LDV-C has previously been reported by us to be the etiological agent of a poliomyelitis (gray matter disease) in genetically susceptible mice (C58 and AKR). We have recently discovered that this same agent induces CNS lesions restricted to the leptomeninges and white matter parenchyma in C57BR/cd mice. Although C57BR/cd mice are closely related to C58 mice, they do not develop poliomyelitis. LDV-C-infected C57BR/cd mice provide a unique animal model for the study of viral-induced CNS inflammatory disease. LDV-C is given by the intraperitoneal route and lesion development is not dependent on immunosuppression. We propose to investigate host genetic, virological and immunology parameters in order to obtain an understanding of the mechanisms involved in the induction of the C57BR/cd specific CNS disease. Association of disease susceptibility with age in C57BR/cd mice will be investigated. Electron microscopy studies will be performed to define the ultrastructure of the white matter lesions during their development. Inheritance of susceptibility to white matter lesions will be studied in F1, F2 and backcross animals obtained from matings between various disease-resistant strains and the C57BR/cd strain. Location of the cells within the CNS which may support virus replication will be investigated by immunofluorescence, electron microscopy, and in situ hybridization techniques. Attempts will be made to increase the incidence and severity of the lesions in C57BR/cd mice by injection of syngeneic spinal cord homogenates. The role of the immune response in the development of C57BR/cd CNS lesions will also be investigated. First, we will determine whether lesions can be induced in neonatally thymectomized, irradiated C57BR/cd mice. Secondly, we will define the immune system component(s) that may mediate lesion development by adaptive transfer of cultured virus-free spleen cells and also investigate whether immunoglobulin produced in LDV-infected C57BR/cd mice reacts with CNS cell antigens.
