https://science.sciencemag.org/content/sci/109/2822/85.full.pdf

Cultivation of the Lansing Strain of Poliomyelitis Virus in Cultures of Various Human Embryonic Tissues

An unusual biphasic central nervous system disease developed in 3-week-old Swiss outbred mice after intracerebral inoculation of the DA strain of Theiler's murine encephalomyelitis virus. Nine to 20 days postinfection 86% of mice became paralyzed, and approximately one-half of these animals survived. During this period neuronal necrosis and microglial proliferation were seen in thalamus, brainstem, and spinal cord. There was an initial phase of virus growth in spinal cord followed by persistent infection at a lower concentration. Virus antigen was readily found in the cytoplasm of neurons by immunofluorescent staining early in the course of infection, whereas after 30 days there was a paucity of cells containing virus antigen which were present only in the spinal cord white matter. Between 1 and 5 months, an intense mononuclear inflammatory cell lesion evolved in the spinal cord leptomeninges and white matter, which coincided with a mild gait disturbance in some surviving mice, and patchy demyelination was found in areas of inflammation. The acute gray matter pathology would appear to be the result of direct virus lytic effect. Although the late white matter lesion culminating in demyelination probably represents a cytocidal infection similar to the situation that exists in certain picornavirus carrier culture systems, a virus-induced immunopathological process merits further study.

Theiler's virus infection in mice: an unusual biphasic disease process leading to demyelination.

The paramyxovirus group is a large one which includes the parainfluenza viruses types 1–5, Newcastle disease, and mumps viruses. Measles, canine distemper, and rinderpest viruses form a distinct subgroup on the basis of antigenicity, hemagglutinating characteristics, and lack of evidence for a virion-associated neuraminidase or neuraminic acid-containing cellular receptors. However, it is now generally accepted that these viruses should also be included in the paramyxovirus group because of their similar structural properties. Other more recently isolated viruses which have been classified as paramyxoviruses on the basis of morphological and biological properties are Yucaipa (Dinter et al., 1964) and Nariva (Walder, 1971) viruses. Table 1 lists paramyxoviruses and their primary hosts.

Reproduction of Paramyxoviruses

Axonal pathology has been highlighted as a cause of neurological disability in multiple sclerosis. The Daniels (DA) strain of Theiler’s murine encephalomyelitis virus infects the gray matter of the central nervous system of mice during the acute phase and persistently infects the white matter of the spinal cord during the chronic phase, leading to demyelination. This experimental infection has been used as an animal model for multiple sclerosis. The GDVII strain causes an acute fatal polioencephalomyelitis without demyelination. Injured axons were detected in normal appearing white matter at 1 week after infection with DA virus by immunohistochemistry using antibodies specific for neurofilament protein. The number of damaged axons increased throughout time. By 2 and 3 weeks after infection, injured axons were accompanied by parenchymal infiltration of Ricinus communis agglutinin I+ microglia/macrophages, but never associated with perivascular T-cell infiltration or obvious demyelination until the chronic phase. GDVII virus infection resulted in severe axonal injury in normal appearing white matter at 1 week after infection, without the presence of macrophages, T cells, or viral antigen-positive cells. The distribution of axonal injury observed during the early phase corresponded to regions where subsequent demyelination occurs during the chronic phase. The results suggest that axonal injury might herald or trigger demyelination.

/pdf/axonal-injury-heralds-virus-induced-demyelination-12vsxwa35x.pdf

Axonal injury heralds virus-induced demyelination.

RECENT STUDIES suggest that viruses may play a role in the etiology of poIymyositis-dermatomyositis. Myxovirus-like structures have been demonstrated in both sarcolemmal nuclei and sarcoplasm of muscle biopsy specimens obtained from a patient with chronic polymyositis.lV2 These structures were observed in 3 specimens taken during an eighteen-month period, suggesting that a chronic virus infection was involved in the pathogenesis of chronic polymyositis. Two other patients with clinicopathological diagnosis of chronic polymyositis demonstrated similar findings.3,4 The complexity and variability of the clinical pictures described in cases of polymyositis does not, however, permit the generalization that the disease might be related to a single etiologic agent. Because many different neurotropic viruses are known to cause muscle infections in mice,6 it seems reasonable to assume that different viral agents may play a pathogenic role in different types of human polymyositis. The present report describes the electron-microscopic findings of numerous intracytoplasmic crystalline arrays resembling those of the picornavirus group in muscle of 2 patients who died after a subacute clinical course of dermatomvositis. CASE REPORTS

Picornavirus-like crystals in subacute polymyositis.

A study has been made of the local effects following intramuscular injection of various neurotropic viruses. Early massive necrosis of muscle fibers accompanied by edema and acute inflammatory reaction is produced by Jungeblut's SK virus even in low concentrations. Similar but more slowly developing lesions follow the introduction of mouse encephalomyelitis GD-VII and FA strains. Strain 4727 (TO type) produces inflammatory changes with fibrosis in the intermuscular septa and necrosis of scattered individual fibers. The relatively avirulent FV strain (TO type) was not pathogenic for skeletal muscle. The Mitchell strain of lymphocytic choriomeningitis virus gives rise to a profuse lymphocytic and monocytic infiltration of the fat and connective tissue but does not cause necrosis of muscle fibers. No significant lesions resulted from intramuscular injection of the murine-adapted human poliomyelitis Lansing virus, the HF strain of herpes, a strain of Eastern equine encephalitis virus, or a still unidentified demyelinating mouse virus. Evidence is presented that the mouse encephalomyelitis virus GD-VII and Jungeblut's SK virus multiply locally in the injected limb. The GD-VII virus has been passed through four muscle to muscle passages and muscle lesions have been elicited at the same time. Specific and complete protection against myositis was obtained by anti-GD-VII and anti-SK rabbit sera.

https://rupress.org/jem/article-pdf/89/1/69/1183958/69.pdf

Myositis in mice following intramuscular injection of viruses of the mouse encephalomyelitis group and of certain other neurotropic viruses

The pattern of actinomycin D-resistant RNA synthesis was examined during primary infection of HeLa cells by virulent Edmonston measles virus and in two HeLa clones persistently infected by the same strain of virus. One of these clones, K11, produces infectious virus of low virulence for HeLa cells, and the other, K11A-HG-1, has thus far failed to yield infectious virus. The patterns of virus-specific RNA synthesized in these three types of infection are qualitatively similar to each other and to the patterns of virus-specific RNA synthesis in other paramyxovirus infections. There were, however, quantitative differences. In addition, virions of the virulent Edmonston strain of measles virus were found to contain high-molecular-weight RNA with a sedimentation constant identical to that of Newcastle disease virus.

/pdf/persistent-infection-of-cells-in-culture-by-measles-virus-41a7dx6w7u.pdf

Persistent Infection of Cells in Culture by Measles Virus III. Comparison of Virus-Specific RNA Synthesized in Primary and Persistent Infection in HeLa Cells

The relation between humoral and cellular immune responses to measles virus in Cercopithecus aethiops monkedy was examined by in vitro virus neutralization and colony inhibition techniques. Both types of specific immune response were maximal two or three weeks after infection and then declined at similar rates for several weeks. However, the humoral response persisted at a low level for at least 44 weeks, whereas the cell-mediated response became undetectable as early as 10 weeks after infection. The cellular response disappeared in three monkeys (including one monkey that produced no detectable circulating antibody) after natural infection as well. Second inoculations with measles virus produced a rise in titer of antibody, but the cellular response was weak or lacking. However, there appeared to be a significant increase in the capacity of lymphocytes from these animals to attach in vitro to measles virus-infected cells. Antiserum to measles virus blocked this phenomenon.

Neutralizing Antibody and Lymphocyte-Mediated, Colony-Forming Inhibition Responses to Measles Infection in Cercopithecus aethiops Monkeys

Summary 1.Following immunization of mice by the intraperitoneal route with active GDVII mouse encaphalomyelitis virus, a marked resistance to myositis and local virus multiplication was obtained against subsequent intramuscular challenge of a standard dose of GDVII virus. In addition, there was no invasion of the central nervous system as evidenced by the absence of signs of disease and histologic changes, and the failure to recover active virus from the spinal cords and brains of mice so challenged. 2.Direct intracerebral challenge of a limited number of mice indicated that an immunity was also established in the central nervous system. However, since small amounts of virus were recovered from the central nervous system tissues of some of the immunized mice at the time of challenge, the occurrence of interference cannot be excluded. 3.Immunization by the subcutaneous and intraperitoneal route also led to the development of complement fixing and neutralizing antibodies in considerable concentrations.

Robert Rustigian

Papers

Myositis in mice following intramuscular injection of viruses of the mouse encephalomyelitis group and of certain other neurotropic viruses

Persistent Infection of Cells in Culture by Measles Virus III. Comparison of Virus-Specific RNA Synthesized in Primary and Persistent Infection in HeLa Cells

Neutralizing Antibody and Lymphocyte-Mediated, Colony-Forming Inhibition Responses to Measles Infection in Cercopithecus aethiops Monkeys

The Resistance of Mice to Myositis and Central Nervous System Infection Following Immunization with GDVII Mouse Encephalomyelitis Virus