Veterinary Science Collected Works - Research Publications
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ItemNo Preview AvailableCAN VIRAL ENVELOPE GLYCOLIPIDS PRODUCE AUTOIMMUNITY, WITH REFERENCE TO THE CNS AND MULTIPLE-SCLEROSIS(BLACKWELL SCIENCE LTD, 1984)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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ItemNo Preview AvailableDO HUMAN T-LYMPHOTROPHIC VIRUSES (HTLVS) AND OTHER ENVELOPED VIRUSES INDUCE AUTOIMMUNITY IN MULTIPLE-SCLEROSIS(WILEY, 1987)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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ItemNo Preview AvailablePATHOGENESIS OF VIRUS-INDUCED DEMYELINATION(ELSEVIER ACADEMIC PRESS INC, 1993)Demyelination is a component of several viral diseases of humans. The best known of these are subacute sclerosing panencephalitis (SSPE) and progressive multifocal leukoencephalopathy (PML). There are a number of naturally occurring virus infections of animals that involve demyelination and many of these serve as instructive models for human demyelinating diseases. In addition to the naturally occurring diseases, many viruses have been shown to be capable of producing demyelination in experimental situations. In discussing virus-associated demyelinating disease, the chapter reviews the architecture and functional organization of the CNS and considers what is known of the interaction of viruses with CNS cells. It also discusses the immunology of the CNS that differs in several important aspects from that of the rest of the body. Experimental models of viral-induced demyelination have also been considered. Viruses capable of producing demyelinating disease have no common taxonomic features; they include both DNA and RNA viruses, enveloped and nonenveloped viruses. The chapter attempts to summarize the important factors influencing viral demyelination, their common features, and possible mechanisms.
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ItemNo Preview AvailableVirus demyelination(SPRINGER, 2003-04)A number of viruses can initiate central nervous system (CNS) diseases that include demyelination as a major feature of neuropathology. In humans, the most prominent demyelinating diseases are progressive multifocal leukoencephalopathy, caused by JC papovirus destruction of oligodendrocytes, and subacute sclerosing panencephalitis, an invariably fatal childhood disease caused by persistent measles virus. The most common neurological disease of young adults in the developed world, multiple sclerosis, is also characterized by lesions of inflammatory demyelination; however, the etiology of this disease remains an enigma. A viral etiology is possible, because most demyelinating diseases of known etiology in both man and animals are viral. Understanding of the pathogenesis of virus-induced demyelination derives for the most part from the study of animal models. Studies with neurotropic strains of mouse hepatitis virus, Theiler's virus, and Semliki Forest virus have been at the forefront of this research. These models demonstrate how viruses enter the brain, spread, persist, and interact with immune responses. Common features are an ability to infect and persist in glial cells, generation of predominantly CD8(+) responses, which control and clear the early phase of virus replication but which fail to eradicate the infection, and lesions of inflammatory demyelination. In most cases demyelination is to a limited extent the result of direct virus destruction of oligodendrocytes, but for the most part is the consequence of immune and inflammatory responses. These models illustrate the roles of age and genetic susceptibility and establish the concept that persistent CNS infection can lead to the generation of CNS autoimmune responses.
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ItemNo Preview AvailableComputer analysis suggests a role for signal sequences in processing polyproteins of enveloped RNA viruses and as a mechanism of viral fusion.(Springer Science and Business Media LLC, 1989-05)We have used a computer program to scan the entire sequence of viral polyproteins for eucaryotic signal sequences. The method is based on that of von Heijne (1). The program calculates a score for each residue in a polyprotein. The score indicates the resemblance of each residue to that at the cleavage site of a typical N-terminal eucaryotic signal sequence. The program correctly predicts the known N-terminal signal sequence cleavage sites of several cellular and viral proteins. The analysis demonstrates that the polyproteins of enveloped RNA viruses--including the alphaviruses, flaviviruses, and bunyaviruses--contain several internal signal-sequence-like regions. The predicted cleavage site in these internal sequences are often known cleavage sites for processing of the polyprotein and are amongst the highest scoring residues with this algorithm. These results indicate a role for the cellular enzyme signal peptidase in the processing of several viral polyproteins. Not all high-scoring residues are sites of cleavage, suggesting a difference between N-terminal and internal signal sequences. This may reflect the secondary structure of the latter. Signal sequences were also found at the N-termini of the fusion proteins of the paramyxoviruses and the retroviruses. This suggests a mechanism of viral fusion analogous to that by which proteins are translocated through the membranes of the endoplasmic reticulum at synthesis.
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ItemNo Preview AvailableTHE V5A13.1 ENVELOPE GLYCOPROTEIN DELETION MUTANT OF MOUSE HEPATITIS-VIRUS TYPE-4 IS NEUROATTENUATED BY ITS REDUCED RATE OF SPREAD IN THE CENTRAL-NERVOUS-SYSTEM(ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS, 1992-03)Following intracerebral inoculation of adult Balb/c Byj mice, the MHV-4 strain of mouse hepatitis virus (MHV) had an LD50 of less than 0.1 PFU, whereas its monoclonal antibody resistant variant V5A13.1 had an LD50 of 10(4.2) PFU. To determine the basis for this difference in neurovirulence we have studied the acute central nervous system (CNS) infection of these two viruses by in situ hybridization. Both viruses infected the same, specific neuroanatomical areas, predominantly neurons, and spread via the cerebrospinal fluid, along neuronal pathways and between adjacent cells. The neuronal nuclei infected and the spread of virus within the brain are described. The main difference between the parental and variant viruses was the rate at which the infection spread. MHV-4 spread rapidly, destroying large numbers of neurons and the animals died within 4 days of infection. The variant virus spread to the same areas of the brain but at a slower rate. This difference in the rate of virus spread was also apparent from the brain virus titers. The slower rate of spread of the variant virus appears to allow intervention by the immune response. Consistent with this, the variant virus spread slowly in athymic nu/nu mice, but in the absence of an intact immune response, infection and destruction of neurons eventually reached the same extent as that of the parental virus and the mice died within 6 days of infection. We conclude that the V5A13.1 variant of MHV-4 is neuroattenuated by its slower rate of spread in the CNS.
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ItemNo Preview AvailableA bioreactor model of mouse tumor progression(HINDAWI PUBLISHING CORPORATION, 2007)The present study represents an investigation of a novel stirred bioreactor for culture of a transformed cell line under defined hydrodynamic conditions in vitro. Cell colonies of the EL-4 mouse lymphoma cell line grown for the first time in a rotating disc bioreactor (RDB), were observed to undergo changes in phenotype in comparison to standard, static flask cultures. RDB cultures, with or without agitation, promoted the formation of adherent EL-4 cell plaques that merged to form contiguous tumor-like masses in longer-term cultures, unlike the unattached spheroid aggregates of flask cultures. Plaques grown under agitated conditions were further altered in morphology and distribution in direct response to fluid mechanical stimuli. Plaque colonies growth in RDBs with or without agitation also exhibited significant increases in production of interleukin-4 (IL-4) and lactate, suggesting an inducible "Warburg effect." Increases in cell biomass in RDB cultures were no different to flask cultures, though a trend toward a marginal increase was observed at specific rotational speeds. The RDB may therefore be a suitable alternative method to study mechanisms of tumor progression and invasiveness in vitro, under more complex physicochemical conditions that may approximate natural tissue environments.
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ItemNo Preview AvailableA presentation of the differences between the sheep and goat genetic maps(E D P SCIENCES, 2005)The current autosomal version (4.2) of the sheep genetic map comprises 1175 loci and spans approximately 3540 cM. This corresponds to almost complete coverage of the sheep genome. Each chromosome is represented by a single linkage group, with the largest gap between adjacent loci being 19.8 cM. In contrast the 1998 goat genetic map (the most recently published) is much less well developed spanning 2737 cM and comprising only 307 loci. Only one of the goat chromosomes appears to have complete coverage (chromosome 27), and 16 of the chromosomes are comprised of two or more linkage groups, or a linkage group and one or more unlinked markers. The two maps share 218 loci, and the maps have been aligned using the shared loci as reference points. Overall there is good agreement between the maps in terms of homologous loci mapping to equivalent chromosomes in the two species, with only four markers mapping to non-equivalent chromosomes. However, there are lots of inversions in locus order between the sheep and goat chromosomes. Whilst some of these differences in locus order may be genuine, the majority are likely to be a consequence of the paucity of genetic information for the goat map.
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ItemInsertion of EGFP into the replicase gene of Semliki Forest virus results in a novel, genetically stable marker virus(SOC GENERAL MICROBIOLOGY, 2007-04)Alphavirus-based vector and replicon systems have been extensively used experimentally and are likely to be used in human and animal medicine. Whilst marker genes can be inserted easily under the control of a duplicated subgenomic promoter, these constructs are often genetically unstable. Here, a novel alphavirus construct is described in which an enhanced green fluorescent protein (EGFP) marker gene is inserted into the virus replicase open reading frame between nsP3 and nsP4, flanked by nsP2 protease-recognition sites. This construct has correct processing of the replicase polyprotein, produces viable virus and expresses detectable EGFP fluorescence upon infection of cultured cells and cells of the mouse brain. In comparison to parental virus, the marker virus has an approximately 1 h delay in virus RNA and infectious virus production. Passage of the marker virus in vitro and in vivo demonstrates good genetic stability. Insertion of different markers into this novel construct has potential for various applications.
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ItemUsing comparative genomics to reorder the human genome sequence into a virtual sheep genome(BMC, 2007)BACKGROUND: Is it possible to construct an accurate and detailed subgene-level map of a genome using bacterial artificial chromosome (BAC) end sequences, a sparse marker map, and the sequences of other genomes? RESULTS: A sheep BAC library, CHORI-243, was constructed and the BAC end sequences were determined and mapped with high sensitivity and low specificity onto the frameworks of the human, dog, and cow genomes. To maximize genome coverage, the coordinates of all BAC end sequence hits to the cow and dog genomes were also converted to the equivalent human genome coordinates. The 84,624 sheep BACs (about 5.4-fold genome coverage) with paired ends in the correct orientation (tail-to-tail) and spacing, combined with information from sheep BAC comparative genome contigs (CGCs) built separately on the dog and cow genomes, were used to construct 1,172 sheep BAC-CGCs, covering 91.2% of the human genome. Clustered non-tail-to-tail and outsize BACs located close to the ends of many BAC-CGCs linked BAC-CGCs covering about 70% of the genome to at least one other BAC-CGC on the same chromosome. Using the BAC-CGCs, the intrachromosomal and interchromosomal BAC-CGC linkage information, human/cow and vertebrate synteny, and the sheep marker map, a virtual sheep genome was constructed. To identify BACs potentially located in gaps between BAC-CGCs, an additional set of 55,668 sheep BACs were positioned on the sheep genome with lower confidence. A coordinate conversion process allowed us to transfer human genes and other genome features to the virtual sheep genome to display on a sheep genome browser. CONCLUSION: We demonstrate that limited sequencing of BACs combined with positioning on a well assembled genome and integrating locations from other less well assembled genomes can yield extensive, detailed subgene-level maps of mammalian genomes, for which genomic resources are currently limited.
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