Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.666307
Title: The recognition of infection in the brain : Toll-like receptor expression and innate immune responses to virus and prion infection
Author: McKimmie, C. S.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2005
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Abstract:
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. Gene transcript levels were first studied in glial cells at rest. Cells were stimulated with bacterial lipopolysaccharide, or by infection with the neuro-invasive 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 microbial-associated molecules. Such a strategy may be an essential requirement for an organ mostly devoid of recognisable immune processes. In 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 up-regulated during viral encephalitis. Furthermore, this response was appropriate to the pathogen, with selective up-regulation of TLRs that sense 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, TLR3 and TLR 9, up-regulation 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. Transmissible spongiform encephalopathies are a group of diseases characterised by chronic neurodegeneration and glial cell activation. This thesis demonstrates that the CNS significantly up-regulated 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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.666307  DOI: Not available
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