Inflammation of the central nervous system (CNS) is important in many human diseases, and is regulated by a multitude of factors, including the cytokine interferon-gamma (IFNgamma). The importance of IFNgamma is highlighted in experimental autoimmune encephalomyelitis (EAE), an animal model of CNS inflammation. Mice lacking IFNgamma show exaggerated disease, with a different pattern of chemokine expression than the wild-type. We administered IFNgamma to the CNS using intrathecal injection of a replication-defective adenoviral vector to ask about direct actions of IFNgamma on chemokine expression without the confounding factors present during CNS inflammation. AdIFNgamma induced expression of CXCL10 and CCL5, two chemokines strikingly absent in Ifng-/- EAE. Chemokine expression was not associated with inflammation, though when an infectious stimulus was administered, an influx of immune cells to the CNS was seen. Using AdIFNgamma to restore IFNgamma to Ifng-/- mice with EAE had a disease-limiting effect. We used vectors encoding CXCL10 or CCL5, to replace these chemokines which are absent during Ifng-/- EAE, attempting to modulate the disease into a form resembling that of the wild-type. AdCCL5 treatment showed a mild reduction in EAE severity in the Ifng-/-, though AdCXCL10 treatment had no effect. A principal inducer of IFNgamma is interleukin-18 (IL 18), and IFNgamma induces IL18-binding protein (IL18bp) which inhibits IL18, establishing a negative feedback loop. We found that ILl8bp expression is upregulated in wild-type mice with EAE, but not in the Ifng-/-, suggesting that the exaggerated disease of the Ifng -/- may be due in part to unrestrained actions of ILI8. Treatment with a vector encoding IL18bp (AdIL18bp) significantly inhibited EAE, without restricting immune cell entry to the CNS. Cytokine expression was shifted away from a pattern favouring Th17 development. AdIL18bp treatment inhibited EAE in Ifng-/- mice, indicating that IFNgamma was not required for this activity. We used a vector encoding M3, a chemokine-binding protein derived from MHV-68, to reduce EAE severity, showing the first use of a viral chemokine-binding protein in EAE.

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The characteristic trait of the Borna disease virus is that it is a complicated single negative stranded RNA virus that is capable of infecting a wide array of mammalian species including human beings. It has been implicated in a diverse variety of human neuropsychiatric diseases. The infection capability, mechanism of infection and range of protein action of this virus remain to be identified. The purpose of the present study was to determine (1) whether the previous Bornaviridae family classification is indeed accurate as the action of BDV indicates that it is related to other viruses and (2) to estimate the number of synonymous (nucleotide substitution) and non-synonymous (amino acid change) evolutionary mutation rates of proteins (nucleoprotein, phosphoprotein, glycoprotein, matrix protein) exhibited by various Borna disease virus host species and the proteins (nucleoprotein, phosphoprotein, glycoprotein, matrix and X protein) of three Borna disease virus strains. The latter study would give an indication as to which proteins are subjected to positive selection. Phylogenetic methods were used to determine the accuracy of the Bornaviridae classification. Phylogenetic trees obtained through an alignment and analysis of the polymerase protein, which displays a uniquely conserved GDN motif, of various RNA negative single stranded viruses using neighbourhood and parsimony methods enabled comparison with other RNA virus families. A method adapted from Ina, (1995) for estimating the synonymous and non-synonymous evolutionary mutation rate was applied to various BDV proteins in order to provide more information on inter (host virus) and intra (virus) mutation rate. This information in turn was used to create an evolutionary model to clarify the positive and neutral evolutionary trend of the inter- and intra-virus proteins examined, which may help clarify and enhance the lack of current knowledge relating to species infection and the epidemiological nature of the virus. The results obtained by the polymerase alignment analysis indicates the presence of two newly discovered BDV motifs, v and vi, confirmed by three diverse alignment programmes. An analysis of the alignment of BDV proteins indicated that the BDV nucleoprotein nuclear localization signal aligns the BDV nucleoprotein between motifs IV and vi of the BDV polymerase. The results obtained by the phylogenetic analysis indicate that the Rabies virus and the Vesicular stomatitis virus are the most closely related animal viruses to BDV, whereas the Rice transitory yellowing (unclassified Rhabdovirus) and Sonchus yellow net plant virus are closet to BDV than other animal Rhabdoviridae raising intriguing questions on the evolutionary origins of the Borna disease virus. The phylogenetic analysis indicates that the Borna disease virus does not fall into a separate Bornaviridae family classification, and suggests that BDV may be more appropriately placed into a separate subfamily in the family Rhabdoviridae. The results of the evolutionary analysis indicate considerable diversity between BDV host virus (inter-species) and BDV virus (intra-species) protein sequences. In the host virus sequence comparison analysis all of the proteins examined displayed a high pattern of non random evolution, which is in contrast to the intra species comparison in which only three proteins; the BDV glycoprotein, nucleoprotein and X protein; displayed a non random pattern of evolution. The positive selection effect displayed by the inter-species (host) proteins may be attributed to antigenic variation displayed by the inter-species sequences and a super infection hypothesis, which indicates that positive selection on host variants could arise during the course of an infection as a result of specific immune responses. The positive and neutral selection trend of the proteins displayed by the intra-species (virus) sequences may be a result of a pattern of nucleotide substitution that is physio-chemically conservative. Conservation may be evident in volume, polarity, hydrophilicity, or molecular weight of amino acids of the proteins. / Thesis (M.Sc.)-University of Natal, Pietermaritzburg, 2002.

The project described in this thesis began with a broad analysis of the changes to amino acid and biogenic amine concentrations in the central nervous system (CNS) during experimental autoimmune encephalomyelitis (EAE) in mice, an animal model of Multiple Sclerosis (MS). That study identified deficits in specific neurotransmitters during EAE that I targeted pharmacologically using the antidepressant drug phenelzine. Phenelzine administration substantially influenced the concentrations of amino acids and biogenic amines in EAE mice in a manner likely to be therapeutic. In the final experiment, I treated EAE mice chronically with phenelzine; This treatment was associated with significant improvements in motor abilities compared to vehicle treated animals. In an open field, improvements were also observed in behavioural indices of depression, physical sickness and anxiety. The results of this thesis may offer new insights into the pathogenesis of EAE and MS and indicate the disease-modifying potential of phenelzine treatment in MS.

Thesis (Ph. D.)--University of Alabama at Birmingham, 2007. / Title from first page of PDF file (viewed Feb. 6, 2008). Includes bibliographical references.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

Lic.-avh. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 3 uppsatser.

Thesis (Ph. D.)--University of Washington, 1999. / Vita. Includes bibliographical references (leaves 118-130).