Show simple item record

dc.contributor.authorMcKimmie, Clive Stewarten
dc.date.accessioned2019-02-15T14:36:21Z
dc.date.available2019-02-15T14:36:21Z
dc.date.issued2005en
dc.identifier.urihttp://hdl.handle.net/1842/35260
dc.description.abstracten
dc.description.abstractThe mechanisms that mediate innate recognition of infections in the immunospecialised environment of the central nervous system (CNS) have not been characterised. This thesis explores the capability of the CNS to detect infections and activate immune responses. The majority of CNS neurones are post-mitotic and cannot be replaced if lost or damaged. Consequently, the resting CNS is devoid of most immune processes, although substantial inflammatory responses can be initiated by specialised glial cells. The innate immune system recognises conserved molecular patterns on microorganisms by a set of pattern recognition receptors which include the Toll-like Receptors (TLR). A growing consensus suggests they are key to the initiation of innate immune responses. Cellular expression of TLR imparts the ability to detect infection and determine pathogen type. A multitude of TLRs have now been cloned, although their function and expression patterns have not been described in the CNS. This thesis aims to explore whether cells of the CNS express TLRs and whether they are capable of responding to different stimuli. To explore gene expression a novel custom microarray was designed, developed and validated to assay the expression of selected gene transcripts involved in innate immune responses. These included a multitude of pattern precognition receptors, in addition to transcripts associated with stress responses and a variety of cytokine, chemokine and interferon (IFN) transcripts. In addition, a highly sensitive quantitative PCR technique was developed. Utilising both techniques this thesis reports the first systematic analysis of TLR gene expression in the CNS.en
dc.description.abstractGene transcript levels were first studied in glial cells at rest. Cells were stimulated with bacterial lipopolysaccharide, or by infection with the neuroinvasive Semliki Forest virus (SFV). Both microglia and astrocytes in culture expressed a multitude of TLRs that were differentially modulated in a specific manner depending on the nature of the stimulus. The expression of TLR suggests glial cells are capable of recognising a vast array of microbialassociated molecules. Such a strategy may be an essential requirement for an organ mostly devoid of recognisable immune processes.en
dc.description.abstractIn vivo, the resting CNS exhibited extensive TLR expression with TLR 3 expressed at exceptionally high levels, comparable to that of lymphoid tissue, but varying with mouse strain. The data reported here show for the first time that TLRs in the brain are upregulated during viral encephalitis. Furthermore, this response was appropriate to the pathogen, with selective up-regulation of TLRs that sense viral infection. Intracerebral inoculation with either SFV or rabies virus initiated substantial upregulation of TLR 2, 3 and 9. Type-I IFN independent mechanisms mediated the up-regulation of TLR 2 following SFV infection, whilst for the two TLRs that mediate recognition of viral nucleic acids, TLR 3 and TLR 9, upregulation of gene expression was dependent upon and proportional to the type-I IFN response. It is likely that by up-regulating TLR 3 and 9, type-I IFN acts to increase the sensitivity of cells in the vicinity of virally infected cells. In this hypothesis, basal levels of TLR detect viral RNA and induce type-I IFN synthesis. This IFN acts in both an autocrine and paracrine way to up-regulate a number of genes including TLR itself. In this way cells in the vicinity of virally infected cells have their virus sensing mechanisms upregulated. This parallels events with protein kinase R, another interferon inducible activator of innate cellular defences.en
dc.description.abstractTransmissible spongiform encephalopathies are a group of diseases characterised by chronic neurodegeneration and glial cell activation. This thesis demonstrates that the CNS significantly upregulated several TLRs, and in the case of TLR 2, by 10-fold towards terminal disease. This response further describes the apparent non-productive innate immune activation of these cells during these diseases. In summary, the finding that the brain has the ability via TLR expression to detect infection and discern its type provides an important contribution to understanding pathological processes in this organ.en
dc.publisherThe University of Edinburghen
dc.relation.ispartofAnnexe Thesis Digitisation Project 2019 Block 22en
dc.relation.isreferencedbyAlready catalogueden
dc.titleThe recognition of infection in the brain: toll-like receptor expression and innate immune responses to virus and prion infectionen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen


Files in this item

This item appears in the following Collection(s)

Show simple item record