ORCID Profile
0000-0002-7694-9509
Current Organisation
University of Leeds
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Publisher: Elsevier BV
Date: 10-2005
DOI: 10.1016/J.BBRC.2005.08.209
Abstract: The resting CNS is an immunospecialized environment, devoid of most immune processes, although substantial inflammatory responses can be initiated. The innate immune mechanisms mediating recognition of CNS infections are unknown. This study provides a comprehensive analysis of Toll-like receptor (TLR) gene expression in the resting and virus-infected murine CNS. TLR transcripts were expressed in the resting CNS with strikingly high expression of TLR 3. Extraneural infection with neuroinvasive Semliki Forest virus resulted in CNS infection followed by rapid selective upregulation of TLR gene expression. Upregulation was independent of T-cell responses. Upregulation of TLR gene expression was also observed following rabies virus infection. TLR upregulation was appropriate to the pathogen and proportional to the virus load. Upregulation of TLR 3 and 9 was dependent upon the type-I interferon response and may act to increase the threshold of sensitivity to detect virus infection in cells surrounding virally infected cells.
Publisher: Caister Academic Press
Date: 2016
Publisher: Microbiology Society
Date: 09-2006
Abstract: To investigate the innate immune response within the brain to lyssavirus infection, key transcripts indicative of innate defences were measured in a mouse model system. Following infection with Rabies virus , transcript levels for type 1 interferons (IFN- α and - β ), the inflammatory mediator interleukin 6 (IL-6) and the antiviral protein Mx1 increased in the brains of mice. Intracranial inoculation resulted in the early detection of virus replication and rapid expression within the brain of the innate immune response genes. Transcripts for type 1 IFNs declined as the disease progressed. Peripheral, extraneural inoculation delayed the host response until virus entered the brain, but then resulted in a large increase in the level of IFN- β , IL-6 and Mx1 transcripts. Induction of this response was also observed following infection with the related European bat lyssaviruses, a group of zoonotic viruses capable of causing fatal, rabies-like disease in mammalian species.
Publisher: Microbiology Society
Date: 12-2007
Abstract: Semliki Forest virus (SFV) infection of the mouse provides a powerful model to study the pathogenesis of virus encephalitis. SFV and other alphavirus-based vector systems are increasingly used in biotechnology and medicine. This study analysed the strong susceptibility of this virus to type I interferon (IFN) responses. Following intraperitoneal infection of adult mice, SFV strain A7(74) was efficiently (100 %) neuroinvasive. In contrast, SFV4 was poorly (21 %) neuroinvasive. Upon entry into the brain, both viruses activated type I IFN responses. As determined by quantitative RT-PCR, activation of the IFN- α gene was proportional to virus RNA load. An intact type I IFN system was required for protection against both strains of SFV. IFN strongly curtailed virus spread in many cell types and in many tissues. In mice with an intact type I IFN system, infected cells were rarely observed and tissue tropism was difficult to determine. In the absence of a functional type I IFN system, the tropism and the potential for rapid and widespread infection of this virus was revealed. Virus infection was readily observed in the myocardium, endocardium, exocrine pancreas, adipose tissue, smooth muscle cells and in the brain in meningeal cells, ependymal cells and oligodendrocytes. In the brains of mice with and without type I IFN responses, virus infection of neurons remained rare and focal, indicating that the previously described restricted replication of SFV A7(74) in neurons is not mediated by type I IFN responses.
Publisher: Elsevier BV
Date: 08-2005
DOI: 10.1016/J.BBRC.2005.06.060
Abstract: The molecular events that underlie prion disease neuropathology remain poorly defined. Within the hippoc us of the ME7/CV mouse scrapie model, profound CA1 neuronal loss occurs between 160 and 180 days post-infection (dpi). To elucidate the molecular events that may contribute to this neuronal loss, we have applied Affymetrix high-density oligonucleotide probe arrays to the study of ME7-infected hippoc al gene expression at 170 dpi. The study has identified 78 genes that are differentially expressed greater than 1.5-fold within the preclinical ME7-infected hippoc us prior to the profound late stage glial cell activation. The results indicate oxidative and endoplasmic reticulum (ER) stress, activated ER and mitochondrial apoptosis pathways, and activated cholesterol biosynthesis within the scrapie-infected hippoc us, and offer insight into the molecular events which underlie the neuropathology.
Publisher: Elsevier BV
Date: 12-2005
DOI: 10.1016/J.JNEUROIM.2005.08.006
Abstract: The mechanisms that mediate innate immune recognition of CNS infections are unknown. This study provides a comparison of Toll-like receptor (TLR) gene expression in resting and virus infected CNS cells. N2a neuroblastoma cells expressed TLR 3 but demonstrated no change in TLR gene expression in response to either LPS or virus infection. N9 microglia and differentiated primary astrocytes expressed most TLR genes. TLR 2 expression was highest in N9 microglia and TLR 7 in astrocytes. In both glial cell types, LPS stimulation upregulated pro-inflammatory cytokines, TLR 2 and TLR 3 gene expression but down-regulated other TLR genes. RNA virus infection substantially increased levels of type-I interferon (IFN) and TLR 3 transcripts and to a lesser extent TLR 9 transcripts. Microglia and astrocytes thus have the ability to discriminate between pathogens and elicit an appropriate response.
Publisher: Elsevier BV
Date: 06-2006
DOI: 10.1016/J.JNEUROIM.2006.03.012
Abstract: Glial cells, particularly microglia, are thought to play a pivotal role in initiating and guiding innate immune responses to CNS infections and in perpetuating inflammation and pathology in CNS diseases such as multiple sclerosis and Alzheimer's disease. We describe here the development and use of a new microarray designed to specifically profile transcript expression of innate immunity genes. Microarray analysis validated by quantitative PCR demonstrated an extensive range of pattern recognition receptor gene expression in resting N9 microglia, including Toll-like receptors, scavenger receptors and lectins. Stimulation with LPS or infection with virus modulated pattern recognition receptor, cytokine, chemokine and other innate immune transcripts in a distinct and stimulus-specific manner. This study demonstrates that a single glial cell phenotype has an innate capability to detect infection, determine its form and generate specific responses.
Publisher: Elsevier BV
Date: 06-2016
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Clive McKimmie.