Molecular mechanisms of innate immune signal tranduction by the Toll-like receptor 4

Lead Research Organisation: University of Cambridge
Department Name: Biochemistry

Abstract

Humans have evolved complex and effective ways of fighting infections caused by microbes such as bacteria and viruses, the immune system. Sometimes the immune system goes wrong and this can cause serious diseases such as rheumatoid arthritis and diabetes. Our research aims to understand at a molecular level how the cells of the immune system are able to recognise microbes and the ways in which these cells respond to cause the familiar symptoms of an infection such as fever and tiredness, and to generate specific antibodies that fight the invading microbes. In this programme we will study the way in which immune system cells respond to a powerful toxins and allergens, such as endotoxin or LPS, released by certain types of bacteria during an infection. Although normal responses to endotoxin are an important part of the fight against infection, it can cause a highly dangerous condition called endotoxic shock in patients with severe septicaemia and this pathological response frequently causes organ failure and death. In fact endotoxin shock is responsible for about 135000 deaths every year in Europe alone. The proposed studies should shed light on why endotoxin can produce a beneficial reaction in some conditions and a damaging response in others.

Technical Summary

The discovery of pattern recogniion receptors (PRRs) is one of the most important advances in immunology of the last 20 years. One class of PRRs, the Toll-like receptors (TLRs) are now understood to play critical roles in the initiation of inflammatory responses to infection by viruses, bacteria and other microbial pathogens. TLR4, the receptor for Gram- lipopolysaccharides, is of of particular importance in this regard and recent studies have also implicated it as a key mediator of the sterile and allergic inflammatory responses charcteristic of chronic diseases such as rheumatoid arthritis and asthma.

This Programme Grant has three objectives all of which aim to understand the molecular mechanisms of signal transduction by TLR4 and to use this information to develop novel therapies for sepsis, allergic asthma and sterile inflammation. Firstly we will use structural biology and the emerging technique of single molecule imaging to study the signal transduction process in living cells. This approach will allow us to visualise the formation of transient signalling complexes in real time and define the molecular basis of signalling specificity, the stoichiometry of the constituent subunits and the cooperativity of the signalling process. In the second part of the programme we will use biophysical, biochemical and cell based techniques to determine the mode of action of lipid bearing aeroallergens and the endogenous ligands fibronectin and tenascin C all of which activate or enhance signalling by TLR4. Finally, in collaboration with Pfizer Inc we will determine how at the structural level antagonistic antibodies directed against TLR4 are able to inhibit signalling and use structure based design to develop novel inhibitors of TLR4 for use in the treatment of endotoxic shock and other inflammatory diseases mediated by TLR4.

Publications

10 25 50
 
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 Elion and Black Immunology Catalyst Sabbatical Award
Amount £226,000 (GBP)
Organisation GlaxoSmithKline (GSK) 
Sector Private
Country Global
Start 11/2016 
End 10/2019
 
Description Interdisciplinary Research Grant
Amount £204,000 (GBP)
Funding ID ARUK-IRG2014-13 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2015 
End 01/2018
 
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 Royal Society Wolfson Refurbishment Scheme
Amount £267,000 (GBP)
Organisation The Royal Society 
Sector Academic/University
Country United Kingdom
Start 03/2016 
End 02/2018
 
Description Wellcome Trust Investigator Award
Amount £2,374,355 (GBP)
Funding ID 100321/z/12/z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2013 
End 02/2021
 
Title Signalling assays 
Description Methods for quantifying signalling 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact N/A 
 
Title feld1 
Description preparations of the allergen feld1 
Type Of Material Biological samples 
Year Produced 2011 
Provided To Others? Yes  
Impact Paper in preparation 
 
Description Continued Collaboration with University of Massachusetts Medical Schoo 
Organisation University of Massachusetts
Department University of Massachusetts Medical School
Country United States 
Sector Academic/University 
PI Contribution Continuation of existing collaboration
Collaborator Contribution Provision of cell lines and reagents. Intellectual discussions about our research work.
Impact On going provision of reagents has enabled our publications for this grant.
Start Year 2009
 
Description Doug Golenbock, University of Massachusetts Medical School 
Organisation University of Massachusetts
Department University of Massachusetts Medical School
Country United States 
Sector Academic/University 
PI Contribution I went on sabbatical to the Golenock laboratory for 2 months in 2008
Start Year 2008
 
Description GSK Immunology Catalyst Sabbatical Award 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution GSK have bought out my teaching and administration duties for 3 years. I spend 3 days a week at GSK and have 2 postdoctoral researchers at GSK. I am working on inflammasome biology and Pattern Recognition Receptor research. I intellectually input into several of the GSK therapeutic units.
Collaborator Contribution GSK bought out my teaching and administration duties for 3 years and fund 2 postdoctoral researchers to work with me at GSK
Impact None yet
Start Year 2016
 
Description Genentech Visiting Professorship 
Organisation Genetech, Inc
Country United States 
Sector Private 
PI Contribution I visited Genentech South San Francisco site and performed research in the laboratory there for 9 months. Two of my PhD students also had 3 month internships working with myself and my Genentech collaborators. We learnt new techniques and gained access to new reagents. I intellectually contributed to their inflammasome research program.
Collaborator Contribution My collaborators gave me novel reagents and supported my research during my time in the USA
Impact None yet as the work is still in progress
Start Year 2016
 
Description International and national collaboration with Eicke Laetz 
Organisation University of Massachusetts
Department University of Massachusetts Medical School
Country United States 
Sector Academic/University 
PI Contribution University of Massachusetts Medical School
Start Year 2008
 
Description International and national collaborations with Kate Fitzgerald 
Organisation University of Massachusetts
Department University of Massachusetts Medical School
Country United States 
Sector Academic/University 
PI Contribution Intellectual input and collaborative discussions about common research interests.
Collaborator Contribution Provision of reagents, cell lines and intellectual input to our research.
Impact Publications linked to our research grants have been facilitated by this collaboration.
Start Year 2006
 
Description Luke O'Neill, Trinity College, Dublin 
Organisation Trinity College Dublin
Country Ireland 
Sector Academic/University 
PI Contribution Collaboration with Trinity College, Dublin
Collaborator Contribution Intellectual input Collaborative discussion Transfer of new techniques
Impact Publications
Start Year 2007
 
Description Non-competitive inhibitors of TLR4 
Organisation Pfizer Ltd
Department Immunology and Microbiology
Country United Kingdom 
Sector Private 
PI Contribution Molecular basis of antagonism
Collaborator Contribution Materials (antibodies)
Impact Subject to NDA
Start Year 2010
 
Title Toll-like receptor 4 antagonism for the treatment of Alzheimer's disease and allergic asthma 
Description We identified that amyloid beta and the cat allergen protein FelD1 activate Toll-like receptor 4 to induce inflammation 
IP Reference  
Protection Protection not required
Year Protection Granted
Licensed No
Impact Investment of 4 million pounds by Apollo Therapeutics to identify Toll-like receptor 4 antagonists for potential use in the treatment of Alzheimer's disease
 
Title Image analysis software for tracking cells 
Description Image analysis software for tracking moving cells and for analysis of fluorescence levels in these cells 
Type Of Technology Software 
Year Produced 2016 
Impact Allows analysis of many cells for single cell signaling assays 
URL http://dx.doi.org/10.17863/CAM.6018
 
Company Name Polypharmakos 
Description Spin out company with Monique Simmonds (Kew), Mark Holmes (Cambridge), Duncan Maskell (Cambridge) to screen natural products for antimicrobial and innate immune activity. 
Year Established 2016 
Impact None Yet
Website http://www.polypharmakos.com/
 
Description ANU, Canberra, Australia, "Pattern Recognition Receptor Signalling in response to Infection" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Talk to faculty and students at ANU with associated questions
Year(s) Of Engagement Activity 2018
 
Description Cambridge Alumni Festival 2014: Why cats make you sneeze 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Public engagement

No notable impacts yet
Year(s) Of Engagement Activity 2014
URL http://www.alumni.cam.ac.uk/events/alumni-festival-2014/further-information
 
Description Cambridge Science Fair 2014: Why cats make you sneeze? 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Public engagement

No impact to date
Year(s) Of Engagement Activity 2014
URL http://www.cam.ac.uk/science-festival/2014-festival
 
Description Cambridge Science Fair Panel Discussion 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact I chaired a session and talks and a question and answer session on receptors at the Cambridge Science Fair
Year(s) Of Engagement Activity 2018
 
Description Hudson Innate Immunity Institute, Melbourne, Australia "Pattern Recognition Receptor Signalling in response to Infection" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Talk to faculty and students at the Hudson Institute and associated questions
Year(s) Of Engagement Activity 2018
 
Description Institute for Child Heath, London (2011):Pattern recognition receptors: the key to host recognition of infection or a load of old PAMPs 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Institute for Child Heath, London

no actual impacts realised to date
Year(s) Of Engagement Activity 2011
 
Description Lafferty Debate participant 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Participated in a public debate on "Adaptive Immunity is innately redundant"
Year(s) Of Engagement Activity 2016
 
Description Pattern recognition receptors: the key to host recognition of infection or a load of old PAMPs 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research or patient groups
Results and Impact Invited talk

no actual impacts realised to date
Year(s) Of Engagement Activity 2009
 
Description Pattern recognition receptors: the key to host recognition of infection or a load of old PAMPs 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact Invited talk

no actual impacts realised to date
Year(s) Of Engagement Activity 2009
 
Description Pattern recognition receptors: the key to host recognition of infection or a load of old PAMPs 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research or patient groups
Results and Impact Talk to the University of Maryland, Baltimore, USA

no actual impacts realised to date
Year(s) Of Engagement Activity 2011
 
Description Pattern recognition receptors: the key to host recognition of infection or a load of old PAMPs 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact Invited talk

no actual impacts realised to date
Year(s) Of Engagement Activity 2010
 
Description Pattern recognition receptors: the key to host recognition of infection or a load of old PAMPs 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact Invited talk Institute for Child Health

no actual impacts realised to date
Year(s) Of Engagement Activity 2010
 
Description Pattern recognition receptors: therapeutic targets for allergic as well as infectious diseases 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research or patient groups
Results and Impact Invited talk CIMR

no actual impacts realised to date
Year(s) Of Engagement Activity 2011
 
Description Pattern recognition receptors: therapeutic targets for allergic as well as infectious diseases 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach local
Primary Audience Participants in your research or patient groups
Results and Impact Invited talk at Cambridge Institute for Medical Research, Cambridge.

no actual impacts realised to date
Year(s) Of Engagement Activity 2011
 
Description Queens College Academic Saturday 2014: Why cats make you sneeze 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Public engagement

No notable impact yet
Year(s) Of Engagement Activity 2014
URL http://www.queens.cam.ac.uk/life-at-queens/news-and-events/academic-saturday-11th-october
 
Description Recognition of bacterial infection by Pattern recognition receptors 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research or patient groups
Results and Impact Invited talk NIAID/NIH

no actual impacts realised to date
Year(s) Of Engagement Activity 2011
 
Description Recognition of bacterial infection by Pattern recognition receptors 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research or patient groups
Results and Impact NIH NIAID, Bethesda, USA

no actual impacts realised to date
Year(s) Of Engagement Activity 2011
 
Description Recognition of bacterial infection by Pattern recognition receptors 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research or patient groups
Results and Impact Invited talk

no actual impacts realised to date
Year(s) Of Engagement Activity 2011
 
Description Recognition of bacterial infection by Pattern recognition receptors 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research or patient groups
Results and Impact Talk to University of Massachusetts Medical School, Worcester, USA

no actual impacts realised to date
Year(s) Of Engagement Activity 2011
 
Description The University of Brisbane, Australia "Pattern Recognition Receptor Signalling in response to Infection" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Talk to faculty and students at the The University of Brisbane with associated questions
Year(s) Of Engagement Activity 2018
 
Description Trinity College Dublin "Pattern Recognition Receptor Signalling in response to Infection" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Talk to the faculty members and students at Trinity College Dublin plus associated questions
Year(s) Of Engagement Activity 2018
 
Description University of Baltimore "Pattern Recognition Receptor Signalling in response to Infection" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Talk to faculty and students at the University of Baltimore and responded to associated questions
Year(s) Of Engagement Activity 2018
 
Description University of Maryland, USA: Pattern recognition receptors: the key to host recognition of infection or a load of old PAMPs 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Invited talk at University of Maryland, USA

no actual impacts realised to date
Year(s) Of Engagement Activity 2011
 
Description University of Strasbourg, France "Bacterial recognition by Pattern Recognition Receptors" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Talk to postgraduate students at the University of Strasberg
Year(s) Of Engagement Activity 2018
 
Description University of Trondheim, Norway "Bacterial recognition by Pattern Recognition Receptors" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Talk (and answered questions in response to talk) to students and researchers at the University of Trondheim in Norway.
Year(s) Of Engagement Activity 2018
 
Description Walter and Eliza Hall Institute for Medical Research, Melbourne, Australia "Pattern Recognition Receptor Signalling in response to Infection" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Talk to faculty members and students at Walter and Eliza Hall Institute for Medical Research with associated questions
Year(s) Of Engagement Activity 2018