Characterisation and therapeutic modulation of toll-like receptor signalling in response to the intracellular pathogen F. tularensis
type: CreativeWork
description: The induction of an innate immune response upon infection is dependent on the detection of the invading organism and the generation of a signalling cascade leading to the production of inflammatory mediators. Toll-like receptors are expressed on multiple cell types and induce the activation of a complex network of signalling pathways containing numerous branches with multiple interactions and cross-talk between the different branches. The TLR system is integral to the generation of a protective immune response and as such is an important target for pathogen-associated modulation. Many bacterial and viral pathogens employ strategies for interrupting or modulating TLR signalling to evade the host immune response. The obligate intracellular bacterial pathogen, F. tularensis, successfully invades and replicates within immune and epithelial cells. However, despite significant research the exact mechanisms used by this pathogen to successfully evade the host immune response remain elusive. To establish the exact signalling events that occur within a host upon infection with F. tularensis, the activation of specific signalling proteins was characterised using in vitro and in vivo models. The MAPKs, ERK and p38, were identified as critical in generating the host response. Furthermore, the temporal regulation of these signalling proteins was found to be bi-phasic with an early transient activation of both ERK and p38 followed by a sustained activation of ERK and a suppression of p38 activation at later time points. The role of ERK was investigated further using a specific inhibitor (PD0325901). Although there was no decrease in bacterial burdens in vitro and no increase in survival in mice treated with PD0325901, the inhibition of ERK activation reduced the secretion of TNF and IL-6 and reduced systemic bacterial proliferation in vivo. The induction of immune signalling cascades requires the activation of one or more receptors. The contribution of TLR2, TLR4 and TLR9 to the …
abstract: The induction of an innate immune response upon infection is dependent on the detection of the invading organism and the generation of a signalling cascade leading to the production of inflammatory mediators. Toll-like receptors are expressed on multiple cell types and induce the activation of a complex network of signalling pathways containing numerous branches with multiple interactions and cross-talk between the different branches. The TLR system is integral to the generation of a protective immune response and as such is an important target for pathogen-associated modulation. Many bacterial and viral pathogens employ strategies for interrupting or modulating TLR signalling to evade the host immune response. The obligate intracellular bacterial pathogen, F. tularensis, successfully invades and replicates within immune and epithelial cells. However, despite significant research the exact mechanisms used by this pathogen to successfully evade the host immune response remain elusive. To establish the exact signalling events that occur within a host upon infection with F. tularensis, the activation of specific signalling proteins was characterised using in vitro and in vivo models. The MAPKs, ERK and p38, were identified as critical in generating the host response. Furthermore, the temporal regulation of these signalling proteins was found to be bi-phasic with an early transient activation of both ERK and p38 followed by a sustained activation of ERK and a suppression of p38 activation at later time points. The role of ERK was investigated further using a specific inhibitor (PD0325901). Although there was no decrease in bacterial burdens in vitro and no increase in survival in mice treated with PD0325901, the inhibition of ERK activation reduced the secretion of TNF and IL-6 and reduced systemic bacterial proliferation in vivo. The induction of immune signalling cascades requires the activation of one or more receptors. The contribution of TLR2, TLR4 and TLR9 to the …
author: Saint, Richard
language: eng
keywords: Francisella, Toll-like receptor, Tularensis
license: https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/f9063fec-7858-43a1-a37f-b1d0d64851d8/download
license: http://creativecommons.org/licenses/by/2.0/uk/
date published: 2013-01-08
date modified: 2026-07-22T22:24:14Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.16357