R. Watanabe

Adoptive transfer of EAE-like lesions from rats with coronavirus-induced demyelinating encephalomyelitis

Viruses have been found to induce inflammatory demyelinating lesions in central nervous system (CNS) tissue of both animal and man, either by natural infections or after vaccination1,2. At least two different pathogenic mechanisms have been proposed for these changes, a cytopathic viral infection of oligodendroglia cells with subsequent cell death, and a host immune reaction against virus and brain antigens. We now report the occurrence of cell-mediated immune reactions against basic myelin proteins in the course of coronavirus infections in Lewis rats. Infection of rats with the murine coronavirus JHM leads to demyelinating encephalomyelitis developing several weeks to months post-infection3–7. Lymphocytes from these diseased Lewis rats can be restimulated with basic myelin protein (BMP) and adoptive transfer of these cells leads to lesions resembling those of experimental allergic encephalomyelitis (EAE) in recipients, which can be accompanied by a mild clinical disease. This model demonstrates that a virus infection in CNS tissue is capable of initiating an autoimmune response which may be of pathogenic importance.

Relapsing subacute demyelinating encephalomyelitis in rats during the course of coronavirus JHM infection

Abstract Temperature-sensitive mutants of the murine coronavirus JHM induced a subacute demyelinating encephalomyelitis (SDE) in young rats. Neurological symptoms were associated with marked lesions of primary demyelination in the white matter of the central nervous system (CNS), and developing after an incubation time of several weeks to months. Many rats survived this infection and recovered completely from this CNS disease. Among 43 survivors of SDE, 9 rats developed a relapse 27–153 days after onset of the first attack. Neuropathological examination of these animals revealed areas of fresh demyelination together with old remyelinated lesions. Viral antigens were detectable in the neighbourhood of fresh lesions and in some cases infectious virus was re-isolated from rats revealing low antibody titers to JHM virus. These results demonstrate that mutants of JHM virus can induce a relapsing demyelinating disease process, associated with a persistent infection, which possesses some similarities to chronic experimental allergic encephalomyelitis.

Analysis of the intrathecal humoral immune response in Brown Norway (BN) rats, infected with the murine coronavirus JHM

Abstract Serum and CSF specimens from clinically healthy Brown Norway (BN) rats inoculated intracerebrally with corona virus JHM were analysed with respect to the state of the blood-brain barrier (BBB) and the intrathecal synthesis and isoelectric distribution of immunoglobulins (Ig). Increased CSF/serum ratios for Ig in the context of an intact BBB were never seen in the absence of intrathecal synthesis of virus-specific antibodies. Affinity-mediated immunoblot analysis revealed a broad pattern of virus-specific antibodies with embedded clusters of restricted heterogeneity, but no signs of oligoclonal Ig production carrying non-viral specificity. From these data it was concluded that BN rats do control the intracerebral spread of JHM virus effectively by a strong local virus-specific antibody response, thereby preventing a clinically apparent disease.

Murine coronavirus-induced encephalomyelitides in rats: Analysis of immunoglobulins and virus-specific antibodies in serum and cerebrospinal fluid

Abstract The humoral intrathecal immune response in coronavirus-induced demyelinating encephalomyelitis in rats associated with an autoimmune reaction to brain antigen, was analysed. The CSF of these animals revealed immune reactions which were directed against coronavirus and other, unknown, antigens. In general, no direct correlation between the disease, the state of the blood-brain barrier (BBB), intrathecal synthesis of Ig and the presence of virus-specific antibodies was detectable, suggesting that the humoral, in contrast to the cellular, immune response does not play a significant pathogenetic role in this CNS disease.

Mechanisms and consequences of virus persistence in the human nervous system.

The central nervous system (CNS) consists of highly complex tissues. Although intracellular communication is observed throughout the body, nowhere else does this property take on such significance and reach such a level of refinement. Cells of nervous tissue possess an unusual morphology and are highly elongated or branched to maximize cell/cell contacts, and cell membranes reveal a spectacular degree of specialization. The metabolism of these neuro-functional cells is rendered subservient to cell function, and cell division does not occur. It is therefore to be expected that persistent infection by viruses could have a profound effect on cell function. The production of viral proteins and their insertion into cell membranes could disrupt vital processes, and render the cells susceptible to immunological attack. Since neuronal tissue does not divide, cells destroyed either by immune responses or directly by the virus cannot be replaced. Similarly, damage induced in supportive tissue could also affect the neurons and so the function of the CNS as a whole could be impaired. It is the purpose of this review to consider briefly the mechanisms by which viruses may persist in the CNS and to assess the effects of this process. To this end we shall consider events in the human CNS, although results obtained from animal experiments will be discussed where relevant. In the context of this discussion, a persistent infection is any infection that is not eliminated by the host immune response. This definition therefore encompasses persistent infections that may be termed latent or slow virus infections.

Coronavirus JHM-Induced Demyelinating Encephalomyelitis in Rats: Influence of Immunity on the Course of Disease

Publisher Summary Disease processes of the central nervous system (CNS) accompanied by demyelination may be the result of a viral infection or the consequence of an immunopathological reaction directed against myelin. In acute viral infections, the infection of oligodendroglial cells, leading to cell destruction, may be the main mechanism for inducing this neuropathological lesion. In the case of a persistent virus infection in oligodendroglia cells, however, it is conceivable that functional impairment of oligodendroglia cells, or the induction of an immune reaction to the agent that may cross-react with brain antigens, could eventually cause demyelination. Therefore, pathogenic studies on subacute or chronic demyelinating encephalomyelitides in association with viral infections may provide information on the mechanisms involved in demyelination. In rats, depending on the biological property of the virus material used, the genetic background and immune response of the host, a subacute or late demyelinating encephalomyelitis can be induced, accompanied by primary demyelination. This provides a model for analysis of the virus and host factors interacting in the pathogenesis of these diseases.

Virological and Immunological Aspects of Coronavirus Induced Subacute Demyelinating Encephalomyelitis in Rats

Infection of rats with the murine coronavirus JHM led to acute or subacute encephalitis. Viral and host factors greatly influenced the outcome of the infection. A number of temperature-sensitive (ts) mutants was obtained which differed widely in their capacity to induce lesions of the central nervous system (CNS) in rats. Under defined conditions a subacute demyelinating encephalomyelitis ( SDE ) with pronounced clinical signs was observed 14-160 days post infection (p.i.). A number of rats, which showed a remission of SDE later developed a relapse of the disease accompanied by neurological symptoms. Neuropathological examination of such animals revealed lesions of active demyelination and extended remyelinated areas. The presence of viral antigen or infectious virus in the CNS of these rats demonstrated that they were persistently infected. Further investigations indicated that this virus infection triggers a cell mediated immune response against basic myelin protein which may contribute to the development of subacute to chronic encephalomyelitides .

Coronavirus-JHM-induced demyelinating encephalomyelitis in rats. Analysis of the intrathecal immune response.

Disease processes of the central nervous system (CNS) accompanied by demyelination may be the result of a viral infection or the consequence of an immunopathological reaction directed against myelin (ter Meulen and Hall, 1978 ; Wisniewski, 1977; Weiner and Stohlman, 1978). In acute viral infections it has been assumed that the infection of oligodendroglial cells, leading to cell destruction, may be the main mechanism for inducing this neuropathological lesion. In the case of a persistent virus infection in oligodendroglia cells, however, it is conceivable that functional impairment of oligodendroglia cells, andlor the induction of an immune reaction to the agent which may cross-react with brain antigens, could eventually cause demyelination. Therefore, pathogenic studies on subacute or chronic demyelinating encephalomyelitides in association with viral infections may provide information on the mechanisms involved in demyelination. In connection with this, infections by murine coronaviruses are of increasing interest (Wege et al., 1982). Strain JHM is known for its ability to cause demyelinating encephalomyelitis in different animal species (Cheever et al., 1949 ; Bailey et al., 1949 ; Weiner, 1973 ; Powell and Lampert, 1975; Fleury, 1980). Additionally, the virus has a tendency to cause chronic infections accompanied by demyelination (Herndon et al., 1975 ; Stohlman and Weiner, 1981). In rats, depending on the biological property of the virus material used, the genetic background and immune response of the host, a subacute or late demyelinating encephalomyelitis can be induced, accompanied by primary demyelination (Nagashima et al., 1978, 1979; Sorensen et al., 1980). This provides a model for analysis of the virus and host factors which interact in the pathogenesis of these diseases. In this chapter the results of our studies are summarized.

Pathogenic Aspects of Murine Coronavirus Infection in Rats

Coronaviruses are a group of agents which are widespread in nature and associated with a great variety of acute, subacute and chronic disease processes of clinical and economic importance. In mice and rats subacute and chronic CNS diseases have been observed as a result of a persistent viral infection. In rats, the disease course is of remitting and relapsing nature accompanied by demyelination. Virological and immunological studies suggest that the persistent virus infection in brain tissue induces an autoimmune response to brain antigens which contribute to the disease process.