Swiss A2G mice were infected intraperitoneally with an avirulent strain of Semliki Forest virus. The virus titres in the optic nerves, retina and brain were estimated on post-inoculation days 3 to 8. High titres of virus were obtained in the optic nerve, retina and brain. The optic nerves, retina and brain were studied by light microscopy up to post-inoculation day 67. Electron microscope studies wee carried out on the optic nerve on post-inoculation days 11 and 14. Inflammatory, microcystic changes and demyelination seen in the optic nerve were similar to those found in he central nervous system.

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Demyelination induced in mice by avirulent Semliki Forest virus. II. An ultrastructural study of focal demyelination in the brain.

Four-week-old mice were infected intraperitoneally with an avirulent strain A7(74) of Semliki Forest virus (SFV) and killed at 4, 10, 15, 21 and 29 days after inoculation. Focal demyelinating lesions were present by 10 days. These were usually accompanied by a mononuclear infiltrate which included lymphocytes possessing characteristic cytoplasmic projections. These latter extended deep into the cytoplasm of adjacent cells, which were usually astrocytes and macrophages. Other features of the focal lesions were expansion of the extracellular space and demyelination which appeared to be fragmentation or lysis rather than stripping of myelin by macrophages. Although healing occurred in some mice after 4 weeks, acute lesions were still found in others of the same age. It was concluded that the demyelination probably had an immunological basis, and interaction between elements of the immune system and glial cells was a factor which inhibited orderly remyelination of the relatively mild lesions resulting from this infection.

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Virus titres and persistently raised white cell counts in cerebrospinal fluid in mice after peripheral infection with demyelinating Semliki Forest virus.

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Effect of myocrisin (sodium auro-thio-malate) on the morphogenesis of avirulent Semliki Forest virus in mouse brain: an electron microscopical study.

Adult mice, infected intracerebrally or intraperitoneally with avirulent Semliki Forest virus, do not show mature virus or advanced stages of viral replication in the brain. If myocrisin is given intraperitoneally 3 h before the virus there is enhancement of all stages of viral replication and budding of virus and mature virions are seen. Compared with controls many intracytoplasmic smooth membrane vesicles were seen in the parenchymal cells of the brain treated with myocrisin or with myocrisin and virus. Myocrisin was visible in the brain and has a membrane proliferating effect which may enhance viral synthesis in the early stages of replication, as well as help in the assembly and budding of mature virus. Increased numbers of infiltrating cells were observed in myocrisin treated mice infected with SFV. The formation of mature virus, and its virulence, appears to be related to the degree of membrane proliferation of the brain cells. The inflammation associated with the increased number of infiltrating cells is secondary to this, the whole process promoting the death of the animals rather than survival.

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Can viral envelope glycolipids produce auto-immunity, with reference to the CNS and multiple sclerosis?

Many viruses, with lipid envelopes derived from the host cell membranes, have been implicated in the aetiology of multiple sclerosis (MS), and epidemiological studies support an infectious agent. Alternatively the disease is thought by other workers to be auto-immune in nature, and recently much attention has been focused on immunological sensitivity to glycolipids in MS patients. In this paper it is proposed that CNS demyelination could arise in susceptible individuals (HLA type) from an immune response to glycolipids, triggered by the carrier effect of one or more enveloped neurotropic viruses.

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Do human T-lymphotrophic viruses (HTLVs) and other enveloped viruses induce autoimmunity in multiple sclerosis?

A virally induced autoimmune reaction may be important in the pathogenesis of multiple sclerosis. The role that glycolipids and myelin basic protein presented to the virus may play in this process is considered. The most likely cells to be the source of autoantigens are neurons, myelin and oligodendrocytes. Viral infection of class II-expressing cells and association of the viral envelope autoantigens and the class II molecules could trigger an autoimmune reaction. It is suggested that for MS to develop following a virus infection the virus will need to cause expression of class II antigens on brain cells as well as fulfill the same role as an antigen presenting cell. The part which T-lymphotrophic viruses (HTLVs) and other enveloped viruses may play in this phenomenon is discussed.

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The pathological effect on the central nervous system of mice following single and repeated infections of the demyelinating A7(74) strain of Semliki Forest virus.

The avirulent strain A7(74) of Semliki Forest virus was inoculated intraperitoneally into mice at weekly intervals for 7 weeks. Pathological, virological and serological studies were carried out twice weekly, after each infecting dose. Similar studies were performed on mice that had been given repeated inoculations at 2, 3 or 4 weekly intervals as were a group of control mice given a single dose of SFV. Results showed grossly enhanced central nervous system lesions, in particular the perivascular cuffing and demyelination, after the 2nd and 3rd weekly inoculation. With further injections there was no increase in severity of the lesions and by the eighth inoculation the pathological changes in the brain appeared to have recovered. The maximum and most persistent damage to the brain was seen after the 2nd and 3rd weekly inoculations. As the interval between two SFV inoculations was increased, the lesions in the central nervous system were reduced and protection increased. Virus in the blood was only detectable after the first inoculation and brain virus after the first and second inoculations. Peak IgG antibody levels were seen on day 46 after a single inoculation and day 35 in the multiple inoculations. It was concluded that repeated inoculations of SFV do not produce a relapsing demyelinating disease, but the 7th and 14th day inoculations do enhance the lesions which are seen to persist after the inoculation on the 21st day. In spite of the gross pathological changes inflicted, the brain damage appears to recover.

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Enhancement of demyelination in the central nervous system of Semliki Forest virus infected mice after pretreatment with muramyl dipeptide.

Semliki Forest virus infections in mice produce an encephalitis with demyelination. If before giving the virus the mice are treated with muramyl dipeptide in Freund's incomplete adjuvant, there is a significant increase in demyelination. If ovalbumin is added to the above and then followed after an interval by a second dose of ovalbumin and finally by the virus, the demyelination is further, but only marginally increased. The addition of ovalbumin without muramyl dipeptide in the schedule appears to increase the number of infiltrating cells and to a lesser extent the perivascular cuffing, but does not increase the demyelination as compared to that obtained when Semliki Forest virus is given on its own.

Acetylmuramyl-Alanyl-Isoglutamine↗

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Immunological reaction of the demyelinating Semliki Forest virus with immune serum to glycolipids and its possible importance to central nervous system viral auto-immune disease.

The avirulent demyelinating strain A7(74) of Semliki Forest virus after passage through mouse brain in vivo and mouse brain cell cultures has been shown to react immunologically with immune sera against galactocerebroside, glucocerebroside, total ganglioside and GT1b ganglioside but not against myelin or sulphatide . Semliki Forest virus is known to take host membrane glycolipid into its coat. The importance of the findings is discussed in relation to the production of a possible anti-brain cell auto-immune phenomenon and its implication in a disease such as multiple sclerosis.

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