Structure and function of the Toll-like receptor signalling pathways: key regulators of immune responses.

Lead Research Organisation: University of Cambridge
Department Name: Research Services Division

Abstract

We plan to publicise important outcomes in consultation with the University of Cambridge press office (see http://www.admin.cam.ac.uk/offices/press/intro.html)

Technical Summary

The human Toll-like receptors (hTlrs) are at the frontline of immune defence against bacterial and viral pathogens. They are located on the surface of leucocytes and recognise conserved pathogen associated molecular patterns such as lipopolysaccharides. In response to these stimuli, the hTlrs mediate a signal transduction pathway that leads to the activation of the transcription factors NF?B and interferon response factor 3. This leads to expression of pro-inflammatory cytokines such as tumour necrosis factor and interleukin 1, anti-viral and co-stimulatory molecules. This innate immune response is closely coupled to the development of adaptive immunity and both are required for an effective anti-microbial responses in vertebrates. As hTlrs regulate the production of pro-inflammatory cytokines they are also implicated in important inflammatory diseases such as endotoxin shock and rheumatoid arthritis. In this proposal we seek to understand the signal transduction pathways mediated through hTlrs at a molecular and structural level. We aim to address three key questions in the field. Firstly, how do the extracellular domains of the hTlrs recognise pathogen patterns and how is this molecular recognition linked to signal transduction? Secondly, what is the structure and function of the cytosolic complex that forms in response to receptor activation and how is the downstream signalling pathway regulated? Thirdly, can small molecules that trigger innate immunity such as imidazoquinolines be exploited to break tolerance and induce adaptive immune responses to tumours?

Publications

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Bryant CE (2010) The molecular basis of the host response to lipopolysaccharide. in Nature reviews. Microbiology

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Gangloff M (2005) Conserved mechanisms of signal transduction by Toll and Toll-like receptors. in Journal of endotoxin research

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Gay NJ (2007) Structure and function of Toll receptors and their ligands. in Annual review of biochemistry

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Gay NJ (2006) Toll-like receptors as molecular switches. in Nature reviews. Immunology

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McGettrick AF (2006) Trif-related adapter molecule is phosphorylated by PKC{epsilon} during Toll-like receptor 4 signaling. in Proceedings of the National Academy of Sciences of the United States of America

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Moncrieffe MC (2008) Assembly of oligomeric death domain complexes during Toll receptor signaling. in The Journal of biological chemistry

 
Description BBSRC Equipment Grant
Amount £250,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2007 
End 09/2008
 
Description BBSRC Project Grant
Amount £1,600,000 (GBP)
Organisation CHDI Foundation 
Sector Charity/Non Profit
Country United States
Start 10/2008 
End 12/2012
 
Description International Joint Project
Amount £11,000 (GBP)
Organisation The Royal Society 
Sector Academic/University
Country United Kingdom
Start 10/2008 
End 09/2010
 
Description Wellcome Trust Programme Grant (Structure, mechanism and regulation of Toll receptor membrane complexes)
Amount £1,000,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2007 
End 12/2012
 
Title Signalling assays 
Description Methods for quantifying signalling 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact N/A