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G J Atkins

Publications and source records attributed to G J Atkins.

At least 73 records · Page 4Linked to original sources
PubMed1990

Pathogenicity of Semliki Forest virus for the rat central nervous system and primary rat neural cell cultures: possible implications for the pathogenesis of multiple sclerosis.

The neurovirulent L10 strain of Semliki Forest virus (SFV) causes extensive neuronal damage in the central nervous system (CNS) of infected rats, and is probably the cause of death. The avirulent A7 and M9 strains do not cause extensive neuronal damage, but do induce immune-mediated CNS demyelination. In primary CNS cell cultures derived from rats, L10 multiplies more rapidly in neurons than avirulent strains, but infection with both virulent and avirulent strains causes depletion of oligodendrocytes from mixed glial cell cultures. It is proposed that the immune-mediated demyelination, which follows infection with avirulent strains, is induced by phagocytosis of myelin debris from infected oligodendrocytes, and the presentation of antigens derived from such debris to T-helper lymphocytes. Based on these and previous results, a scheme for the pathogenicity of defined strains of SFV is proposed. The applicability of this scheme to the understanding of human demyelinating disease such as multiple sclerosis is discussed.

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PubMed1989

Effect of infection with the ts22 mutant of Semliki Forest virus on development of the central nervous system in the fetal mouse.

The A7 strain of Semliki Forest virus induces rapid fetal death in pregnant mice, whereas the ts22 mutant derived from it is teratogenic for a proportion of fetuses. Both A7 and ts22 induce viremia and infect the central nervous systems and fetuses of pregnant mice. Using immunogold-silver staining, a cDNA probe for a Semliki Forest virus nonstructural sequence, and a riboprobe derived from the same sequence, we showed that the skin and musculoskeletal systems of fetuses from mothers infected with ts22 were often heavily infected but the central nervous systems were not labeled before day 17 of pregnancy. Damage to the neural tube, including open-neural-tube defects, was detected in fetuses following infection of the mother at days 8 and 10 of pregnancy with both A7 and ts22. For ts22, neural tube damage induced by fetal infection before day 17 of pregnancy appeared to be indirect and caused by virus infection of mesenchymal cells surrounding the developing neural tube.

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PubMed1988

Teratogenicity of the Semliki Forest virus mutant ts22 for the foetal mouse: induction of skeletal and skin defects.

The maximum proportion of skeletal and/or skin defects induced by the Semliki Forest virus (SFV) mutant ts22 in the 17-day-old foetal mouse occurred following infection of the mother at day 10 of pregnancy. The skeletal defects were detected using a combination of Alcian blue staining for cartilage and Alizarin red staining for bone. Using immunogold-silver staining with anti-SFV IgG and in situ hybridization with a cDNA probe to SFV non-structural sequences, we have shown that mesenchymal cells in the dermis and surrounding developing cartilaginous plates were heavily infected in most foetuses at day 17 of pregnancy, following infection of the mother at day 10. Other infected foetal tissues contained less viral antigen and nucleic acid; they included the liver, muscle (including myocardium), lung and kidney. The central nervous system contained only small amounts of viral antigen and nucleic acid. It is proposed that the skeletal and skin defects induced in mouse foetuses by ts22 infection result from the tropism of the virus for mesenchymal cells involved in the development of such tissue.

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PubMed1987

Isolation and preliminary characterization of Semliki Forest virus mutants with altered pathogenicity for mouse embryos.

Four temperature-sensitive (ts) mutants of the A7 strain of Semliki Forest virus (SFV) have been isolated. All mutants were defective in RNA synthesis at the restrictive temperature (39 degrees C) compared to the permissive temperature (30 degrees C). Since the body temperature of mice fluctuates between 37 degrees C and 39 degrees C, multiplication was also examined at 37 degrees C; only the multiplication of ts4 was restricted. After intraperitoneal infection of 8-day pregnant mice, the wild-type induced rapid abortion. Ts4 and ts26 had no effect on embryonic development. Litters born to ts4-infected mothers developed no postnatal immunity whereas 50% of litters from ts26-infected mothers were immune. Unlike the wild-type, ts14 induced the same or higher virus titres in placental tissue in most mice than in foetal tissue. Ts22 and ts14 induced a range of development defects, including developmental arrest, mummification, abortion and postnatal death. Most surviving offspring were immune. Although ts4 induced no viraemia, ts14, ts22 and ts26 induced a lower titre but longer lasting viraemia than the wild-type. It is concluded that infections of pregnant mice with ts14 and ts22 in particular are good models for analysis of the mechanism of virus-induced developmental defects.

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PubMed1986

Infection of cultured early mouse embryos with Semliki Forest and rubella viruses.

Early mouse embryos at the four- to eight-cell stage or the blastocyst stage could be infected with the A7 strain of Semliki Forest virus (SFV) after the removal of the zona pellucida, either by Pronase treatment or following hatching of blastocysts. With SFV, rapid virus production and eventual cytolysis resulted from infection at either stage. For four- to eight-cell embryos the cytopathic effect was delayed and a proportion of embryos developed to the blastocyst stage. Four- and eight-cell embryos could not be infected with rubella virus (RV), even after removal of the zona pellucida. RV infection of zona-free blastocysts resulted in a productive but non-cytolytic infection which did not affect embryonic development to the early egg-cylinder stage. RV did not multiply in inner cell mass cells isolated from embryos at the blastocyst stage, although SFV did multiply in such cells.

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PubMed1985

The pathogenicity of the A7, M9 and L10 strains of Semliki Forest virus for weanling mice and primary mouse brain cell cultures.

The multiplication of the M9, A7 and L10 strains of Semliki Forest virus (SFV), both in weanling mice and primary mouse brain cell cultures, was compared. Following both intraperitoneal (i.p.) and intracerebral (i.c.) injection, the virulent L10 strain multiplied to higher titre in the mouse central nervous system (CNS) than did the less virulent M9 and A7 strains, whereas M9 multiplied to higher titre than A7. By the i.c. route, all three virus strains multiplied to higher titre than following i.p. injection. Multiplication of A7 and M9 in oligodendrocytes, but not neurons, was detected following i.c. injection. All three virus strains showed a tropism for cultured mouse glial cells rather than neurons. The L10 strain multiplied better in neurons than did A7 or M9. It is concluded that the mechanism of acute demyelination induced by the M9 and A7 strains is similar. Based on this and previous studies, it is proposed that infection of glial cells triggers immune-mediated demyelination. The virulence of the L10 strain is due to its ability to exceed a lethal threshold of damage to neurons before immune intervention can occur.

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PubMed1984

The pathogenicity of the M9 mutant of Semliki Forest virus in immune-compromised mice.

The role of immune mechanisms in the pathogenicity of the M9 mutant of Semliki Forest virus (SFV) has been examined by the use of immune-deficient and immune-suppressed mice. In immune-competent BALB/c and C57BL/6 mice, the lesions in the central nervous system (CNS) were characterized by acute demyelinating meningoencephalomyelitis. Myelin vacuolation and demyelination were more severe in BALB/c mice than in mice with a C57BL background. The mortality was 12% and 29% respectively. Treatment with cyclophosphamide or sodium aurothiomalate did not greatly alter the type of lesion produced, although mortality was increased. Lesions were less severe in nude (T-lymphocyte-deficient) mice and more severe in beige (natural killer cell-deficient) mice than in most immune-competent mice. Mortality was marginally increased in nude mice but not in beige mice. Demyelination in nude mice was followed rapidly by remyelination. Immune modification did not significantly alter the titres of virus in the brain at 7 days post-infection and infectious virus had been cleared from the brain by 14 days in all cases. Degenerating oligodendrocytes were detected in the CNS of all immune-modified mice examined at day 7. This study therefore suggests that both immune mechanisms and destruction of oligodendrocytes play a role in the production of demyelination by M9.

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PubMed1983

Oligodendrocyte infection and demyelination produced in mice by the M9 mutant of Semliki Forest virus.

Intraperitoneal inoculation with the M9 mutant of Semliki Forest virus caused focal demyelinating encephalomyelitis in weanling BALB/c and C57BL/6 mice. Demyelination was more severe in BALB/c than in C57BL/6 mice. Virus particles were seen in oligodendrocytes in areas of myelin vacuolation 5 and 7 days post inoculation (DPI). Oligodendrocytes containing virus in BALB/c mice showed hypertrophy and vacuolar degeneration. There was a mononuclear cell infiltrate and lymphocytes and necrotic cells were present in vacuoles in myelin sheaths. Demyelinating plaques containing macrophages laden with myelin debris were most prominent 14 DPI when virus was cleared from the brain. Remyelination of the central type occurred 28 DPI in BALB/c mice. These findings indicate that direct virus-induced injury to oligodendrocytes has a major role in the initiation of inflammation and demyelination in this model system.

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PubMed1983

The avirulent A7 Strain of Semliki Forest virus has reduced cytopathogenicity for neuroblastoma cells compared to the virulent L10 strain.

Molecular and host range properties of the virulent L10 strain of Semliki Forest virus were compared to those of the avirulent A7 strain. No difference could be detected between the two strains in adsorption, nucleocapsid synthesis, protein synthesis, ratio of 42S:26S RNA, particle infectivity, interferon induction and susceptibility, or defective interfering particle production. A7 showed lower total RNA synthesis than L10 in BHK, G26-24 (oligodendroglioma) and C1300 (neuroblastoma) cells. Cytopathogenicity of A7 was reduced compared to L10 in C1300 cells but not in G26-24 cells. It is concluded that the avirulent A7 strain has similar host range and molecular properties to the neurovirulence mutants M9 and M136, and that demyelination may be produced by a similar mechanism.

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PubMed1982

Semliki forest virus neurovirulence mutants have altered cytopathogenicity for central nervous system cells.

We have analyzed the pathogenicity and host range properties of four neurovirulence mutants of Semliki Forest virus which, unlike the wild type (WT), allow the survival of weanling mice injected intraperitoneally with 10(2) PFU. The mutant M9 showed a sustained multiplication in the brains of infected mice. It produced paralysis in 35%, and 8% died. Demyelination occurred in 94% of the surviving mice and was associated with the destruction of oligodendrocytes. All of the mutants showed a restricted ability to multiply in BHK, C1300 (neuroblastoma), and G26-24 (oligodendroglioma) cells as compared with the WT, and this was not associated with differential interferon production or action. C1300 cells infected with the mutants survived, whereas WT-infected cells were killed. In G26-24 cells all of the mutants and the WT produced a rapid cytopathic effect which was inhibited by pretreatment with 10 U of mouse interferon. Extensive RNA synthesis was detected for all of the mutants and the WT in BHK and C1300 cells, but it was only detectable in G26-24 cells in small amounts early in the infection. The mutant M4 had a defect in the nucleocapsid assembly, whereas M9 had a defect in total RNA synthesis. M136 was defective in the synthesis of 26S RNA, and M103 showed defective synthesis of viral core protein in C1300 cells. It is concluded that C1300 cells can tolerate viral RNA synthesis by a defective virus without showing a cytopathic effect, but the fully virulent WT virus is cytopathic. G26-24 cells are sensitive to small amounts of viral RNA synthesis. These properties of the WT and mutant viruses correlate with changes produced in the neurons and oligodendrocytes of the central nervous system: the virulence of the WT is due to its ability to destroy both neurons and oligodendrocytes, whereas the demyelination produced by the mutants M9 and M136 is due to the destruction of oligodendrocytes alone.

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PubMed1982

Effect of alphavirus infection on mouse embryos.

Seven strains and mutants of the alphaviruses, Semliki Forest virus and Sindbis virus, differed in their lethality for mouse embryos and their mothers. The A7 strain and the neurovirulence mutant M103 of Semliki Forest virus were selected for detailed comparison. A7 produced 100% lethality of mouse embryos but was avirulent for their mothers. M103 did not kill embryos or their mothers but did induce postnatal immunity. This immunity could be induced in utero or by suckling to an immune mother. Infectious virus could be recovered from the brain, blood, and embryos of mice infected with A7. Mice infected with M103 developed a viremia of similar titer, but virus could not be recovered from brain or embryos. Electron microscopy showed multiplying virus in trophoblast and fetal tissue after infection with A7, but no virus could be detected in such tissue after infection with M103. Cultures of ectoplacental cone trophoblast cells incubated in the presence of A7 or M103 showed multiplying A7 in the giant cells, but no M103. It is concluded that A7 can traverse both the blood-brain barrier and the placenta, whereas M103 can traverse neither.

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PubMed1981

Demyelination in mice resulting from infection with a mutant of Semliki Forest virus.

Twelve of 34 weanling mice (35%) developed lesions in the brain and spinal cord following i.p. infection with 10(2) p.f.u. of a mutant of Semliki Forest virus (SFV). Six of 12 mice examined 13 days post infection (p.i.) showed meningo-encephalomyelitis with focal spongiform lesions in the grey and white matter. The spongiform lesions were characterised by necrosis of putative oligodendrocytes, myelinic vacuolation and mononuclear cell infiltration. Only one of six mice examined 21 days p.i. and one of six mice examined 28 days p.i. showed lesions which comprised reactive and dystrophic changes in the white matter. Spongiform lesions and pycnotic nuclei were not seen at these times. Viral nucleocapsids were seen in the early stages of the disease in putative necrotic oligodendrocytes. Mature virus particles were not seen. This was in contrast to mice infected with virulent wild-type SFV when lesions were more severe and were accompanied by large numbers of immature and mature virus particles. It is suggested that the demyelination in mice infected with mutant SFV results primarily from selective destruction of oligodendrocytes by the mutant virus.

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PubMed1981

Establishment of persistent infection in mouse cells by Sindbis virus and its temperature-sensitive mutants.

The ability of wild-type (wt) Sindbis virus and six temperature-sensitive (ts) mutants to establish persistent infection in mouse L cells and a line of mouse embryo (ME) cells was determined. The wt established persistent infection in both ME cells and L cells at 39 degrees C. At 30 degrees C the wt established persistent infection in L cells but not ME cells, which did not recover from the initial infection. For the ts mutants, both cell lines survived the initial infection at 39 degrees C (the restrictive temperature) but the virus was eventually eliminated. At 30 degrees C (the permissive temperature) in L cells all mutants established persistent infection. In ME cells at 30 degrees C, RNA- mutants (unable to synthesize virus-specified RNA at 39 degrees C) established persistent infection whereas the cells did not recover from infection with RNA+ mutants (able to synthesize virus-specified RNA at 39 degrees C). The wt virus was less cytopathic in L cells than in BHK or ME cells. Interferon was produced by both L and ME cells at 30 degrees C and 39 degrees C, but its activity could not be detected in either cell line at 30 degrees C. It is proposed that establishment of persistent infection is dependent on reduced cytopathogenicity in the early stage of infection, and that further evolution of the virus then occurs to a less cytopathic form. Elimination of the virus at 39 degrees C is probably due to the action of interferon.

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PubMed1980

Isolation and preliminary characterization of Semliki Forest virus mutants with altered virulence.

Four mutants of Semliki Forest virus (SFV) strain Lio showing altered virulence in weanling mice were selected following mutagenesis with N-nitro-N-methyl-N'-nitrosoguanidine. Intraperitoneal (i.p.) injection of wild-type (wt) virus resulted in the death of all mice given more than 30 p.f.u. Protection of mice surviving injection with lower doses of virus was not obtained. A proportion of mice infected with doses from 10(4) to 10(7) p.f.u. of mutant virus survived infection. Such surviving mice were protected against an otherwise lethal challenge with wt virus. Three mutants which were non-lethal at loses of 10(2) p.f.u. were studied further. The mutants M4 and M103 established a transient viraemia which was quickly cleared; unlike the wild-type, the virus did not enter the brain or spinal cord. The mutant M136 produced a viraemia similar to the wild-type, but reached a lower titre in the brain; it was not recovered from the spinal cord. Severe necrotic and inflammatory lesions, associated with large numbers of virus particles, were present in the brain and spinal cord (CNS) of mice 5 days p.i. with wt virus. Mice infected with M136 showed degenerative lesions in the grey and white matter of the CNS at 13 days p.i. Virus particles could not be detected at this time either by electron microscopy or infectivity assays.

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PubMed1980

Histiolymphocytic lymphosarcoma in the subcutis of two horses.

Two aged mares with histiolymphocytic lymphosarcoma had multiple rapidly proliferating tumours in the subcutis. Consistent haematological changes were absent. One mare had lymph node involvement but no neoplastic lesions in the viscera. Microbiological examination of tumour tissue showed coryneform bacteria; there was no evidence of C-type or lytic viruses or of reverse transcriptase. Prominent intramitochondrial crystalline inclusions were in histiocytic tumour cells.

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PubMed1979

Establishment of persistent infection in BHK-21 cells by temperature-sensitive mutants of Sindbis virus.

Twelve temperature-sensitive (ts) mutants of Sindbis were examined for their ability to establish persistent infection in BHK-21 cells at 39 degrees C. Five of these mutants were able to initiate colony formation in infected cultures, which followed an extensive c.p.e. Two of the mutants were able to establish persistent infections which survived beyond the fifth cell passage p.i. The ability to initiate colony formation was correlated with low reversion of the ts mutation, or with ability to interfer with the multiplication of the wild-type virus. Virus released from persistently infected cultures was not temperature-sensitive. The restriction of virus multiplication in persistently infected cells operated prior to virus-specified RNA synthesis. It is concluded that in this system establishment of persistent infection depends on an inhibition of virus multiplication early in infection and occurs in only a small proportion of infected cells.

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