In a multifactorial setting, infection of mice with the lactate dehydrogenase-elevating virus (LDV) triggers a general fatal polioencephalomyelitis. The disease occurs only in mouse strains (C58 and AKR) that are permissive for expression of endogenous AKR MuLV genomes and are immunosuppressed due to old age and/or treatment with chemicals or X-irradiation. In other mouse strains, LDV establishes only, but invariably, a lifelong asymptomatic persistent infection. The goal of our proposal is to elucidate the mechanism by which an acute infection with LDV triggers the paralytic disease and the roles of AKR MuLV and immunosuppression play in rendering C58 mice susceptible to this motor neuron disease. We have demonstrated by in situ hybridization with LDV cDNA probes that the development of paralysis coincides with the appearance of LDV RNA in spinal cord motor neurons. Furthermore, Northern blots with AKR MuLV-specific probes indicate that the expression of 3-kb AKR MuLV RNA increases specifically in the spinal cord of C58 mice with increase in age and after immunosuppression. In situ hybridization with these probes indicates the presence of the retroviral RNA in motor neurons. On the basis of these results, we hypothesize that AKR MulV expression in motor neurons generates an alternate LDV receptor on the surface of these cells. Cytocidal infection of these neurons by LDV then results in their destruction and paralysis. The LDV receptor on neurons is postulated to differ from that of macrophages, which is the primary LDV permissive cell in mice, since anti-LDV antibodies prevent the infection of neurons without affecting the infection of macrophages. Our proposed research is designed to further test this hypothesis and ultimately identify the MuLV-controlled LDV receptor on neurons and the domain of the glycoprotein of LDV that is responsible for the interaction with this receptor. We anticipate that the concepts developed in our study of the interaction of two viruses in motor neuron disease may have more general applicability to other human and animal diseases.
