The neurotropic murine coronavirus, MHV-JHM (JHMV) causes encephalitis and paralytic-demyelinating disease in susceptible strains of mice and rats. The neuropathological features of JHMV infection have been widely used as a model for the study of human demyelinating diseases such as multiple sclerosis (MS), for which the etiology has not yet been established. Although the mechanism by which JHMV induces demyelination is not known, the final pathological outcome of most virus infections depends on dynamic balance between virus replication and the ability of the host to resist or control the infection. Control of virus replication can be accomplished by the host immune response, or by activation of intrinsic cellular resistance mechanisms, such as interferon production. Recently, we have found that intracerebral administration of the naturally occurring opioid peptide, beta-endorphin (beta-end) protects mice from JHMV-induced paralytic-demyelinating disease. Protection was accompanied by significantly reduced virus replication in the central nervous system (CNS) as early as three days post-infection (p.i.), suggesting that beta-end stimulates or promotes host resistance to virus infection. The possibility that the immune response is involved in the protective effect is supported not only by preliminary data indicating that protection does not occur in irradiated, or immunoincompetent mice, but also in previously published data which confirm a critical role for the immune response in the control of virus growth during JHMV infection. In addition, intracerebral beta-end administration resulted in significantly enhanced JHMV-specific proliferation of lymphocytes prepared from the cervical lymph nodes of infected mice. However, it is not known whether beta-end is capable of activating intrinsic cellular resistance to reduce virus replication. Thus, the primary purpose of the proposed studies is to identify the relative roles of immune-mediated and intrinsic resistance in the protective effect of beta-end. This will be accomplished in the first two specific aims, which seek to identify mechanisms by which beta-end treatment promotes a specific or nonspecific anti-viral immune response in the central nervous system (Aim 1) or results in host cell resistance to virus infection and subsequent replication (Aim 2). Subsequent experiments are planned to define the pharmacological parameters of the protective effect. These studies offer a unique opportunity to investigate the ability of the CNS to resist virus-induced disease. More importantly, they offer considerable potential for the design of successful strategies for the treatment of virus-induced and immune- mediated demyelination.
