Cell-autonomous and innate immunity

Lead Research Organisation: MRC Laboratory of Molecular Biology

Abstract

Our research focuses on the immune system and the mechanisms which it has for recognising infectious organisms. Toll-like receptors (TLR) are essential for our immune system because they can detect bacterial and other infections at an early stage. Their activation then signals to the cell nucleus to activate genes required for the immune response against the invader. NF-?B is arguably the most important signalling molecule in this scenario. Its activation is finely tuned and any dysregulation has the potential to cause disease. For example, incomplete activation of NF-?B may allow infections to proceed while its excessive activation may induce septic shock or autoimmunity. ||To understand the signalling cascades and learn how to manipulate them to our advantage, we have engineered a mammalian cell line to become an NF-kB reporter. Using this cell line and genetic techniques, we wish to identify essential components of TLR and related signalling pathways.

Technical Summary

Genetic screens have contributed significantly to our current understanding of biology. While screens in mammals promise the most direct insight into human biology and disease, due to the long mammalian generation time and the associated high costs, screens have been mainly performed in lower organisms. For cell-autonomous traits, however, these difficulties may be circumvented by genetically analyzing somatic cell lines. As somatic cell genetics seems to offer a significant and largely untapped potential for understanding mammalian signal transduction, we propose a program consisting of forward and reverse screens investigating Toll-like receptors (TLRs) and NF-k B.

Publications

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Bloor S (2010) Endoplasmic reticulum chaperone gp96 is essential for infection with vesicular stomatitis virus. in Proceedings of the National Academy of Sciences of the United States of America

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Bloor S (2008) Signal processing by its coil zipper domain activates IKK gamma. in Proceedings of the National Academy of Sciences of the United States of America

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Boyle KB (2016) TBK1 directs WIPI2 against Salmonella. in Autophagy

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Boyle KB (2019) Measuring Antibacterial Autophagy. in Methods in molecular biology (Clifton, N.J.)

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Boyle KB (2015) Rubicon swaps autophagy for LAP. in Nature cell biology

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Boyle KB (2012) Activation of the neutrophil NADPH oxidase by Aspergillus fumigatus. in Annals of the New York Academy of Sciences

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Boyle KB (2013) The role of 'eat-me' signals and autophagy cargo receptors in innate immunity. in Current opinion in microbiology

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Falcon B (2018) Galectin-8-mediated selective autophagy protects against seeded tau aggregation. in The Journal of biological chemistry

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Randow F (2009) Viral avoidance and exploitation of the ubiquitin system. in Nature cell biology

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Randow F (2006) Retroviral transduction of DT40. in Sub-cellular biochemistry

 
Description External Member Swiss National Research Council, Division of Biology and Medicine
Geographic Reach Europe 
Policy Influence Type Membership of a guideline committee
 
Description member Wellcome Trust expert review group immunology
Geographic Reach National 
Policy Influence Type Participation in advisory committee
Impact .
 
Description AMS/Wellcome Trust Clinical Lectureship
Amount £29,790 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2009 
End 11/2013
 
Description Boehring Ingelheim Fonds Studentship (VD)
Amount € 40,400 (EUR)
Organisation Boehringer Ingelheim Foundation 
Sector Charity/Non Profit
Country Germany
Start 08/2020 
End 08/2022
 
Description Boehringer PhD Studentship Stipend Pathe
Amount £85,000 (GBP)
Organisation Boehringer Ingelheim 
Sector Private
Country Germany
Start 02/2015 
End 01/2018
 
Description César Milstein Memorial studentship of the Darwin Trust, Edinburgh
Amount £72,000 (GBP)
Organisation British Society for the History of Science (BSHS) 
Department Darwin Trust of Edinburgh
Sector Charity/Non Profit
Country United Kingdom
Start 10/2008 
End 09/2011
 
Description Cambridge International Scholarship - VD
Amount £110,000 (GBP)
Organisation University of Cambridge 
Sector Academic/University
Country United Kingdom
Start 10/2019 
End 09/2022
 
Description Cambridge Overseas Trust, Studentship stipend
Amount £72,000 (GBP)
Organisation University of Cambridge 
Sector Academic/University
Country United Kingdom
Start 10/2007 
End 09/2010
 
Description Celltech Studentship (fees) - Pathe
Amount £21,000 (GBP)
Organisation Medical Research Council (MRC) 
Department Medical Research Foundation
Sector Charity/Non Profit
Country United Kingdom
Start 02/2015 
End 01/2018
 
Description Darwin Trust Studentship - Karpiyevich
Amount £86,000 (GBP)
Organisation British Society for the History of Science (BSHS) 
Department Darwin Trust of Edinburgh
Sector Charity/Non Profit
Country United Kingdom
Start 10/2011 
End 09/2014
 
Description Hugh Pelham Fellowship - Mund
Amount £148,500 (GBP)
Organisation Medical Research Council (MRC) 
Department Medical Research Foundation
Sector Charity/Non Profit
Country United Kingdom
Start 09/2019 
End 08/2022
 
Description NACC Medical Research Award 2011
Amount £73,110 (GBP)
Organisation National Association for Colitis and Crohn’s Disease (NACC) 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2011 
End 09/2013
 
Description University of Cambridge Medical Studentship
Amount £62,583 (GBP)
Organisation University of Cambridge 
Department Cambridge Institute for Medical Research (CIMR)
Sector Academic/University
Country United Kingdom
Start 10/2011 
End 09/2014
 
Description Wellcome Trust Senior Investigator Award
Amount £1,011,565 (GBP)
Funding ID 104752/Z/14/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2015 
End 06/2021
 
Description Role of GBPs in bacterial infection 
Organisation Yale University
Country United States 
Sector Academic/University 
PI Contribution Mechanistic investigation on the role of GBPs in transforming cytosolic bacteria into caspase activation platforms
Collaborator Contribution Mouse experiments to validate our mechanistic discoveries in vivo
Impact PMID: 32541830
Start Year 2020
 
Description how poxvirus subverts innate immunity 
Organisation Imperial College London
Department Faculty of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution expertise in innate immune signalling
Collaborator Contribution experts in poxvirus biology
Impact Chen, R.A., Ryzhakov, G., Cooray, S., Randow, F., and Smith, G.L. (2008). Inhibition of IkappaB Kinase by Vaccinia Virus Virulence Factor B14. PLoS Pathog 4, e22. Bloor S, Maelfait J, Krumbach R, Beyaert R, Randow F. (2010) Endoplasmic reticulum chaperone gp96 is essential for infection with vesicular stomatitis virus. Proc Natl Acad Sci U S A 107, 6970-5.
Start Year 2007
 
Description somatic cell genetics 
Organisation University of Cambridge
Department Cambridge Institute for Medical Research (CIMR)
Country United Kingdom 
Sector Academic/University 
PI Contribution vector biology, design of screens, somatic cell genetics
Collaborator Contribution mass spectrometry, membrane biology
Impact Duncan, L.M., Timms, R.T., Zavodszky, E., Cano, F., Dougan, G., Randow, F., and Lehner, P.J. (2012). Fluorescence-based phenotypic selection allows forward genetic screens in haploid human cells. PLoS ONE 7, e39651. Weekes, M.P., Antrobus, R., Talbot, S., Hör, S., Simecek, N., Smith, D.L., Bloor, S., Randow, F., and Lehner, P.J. (2012). Proteomic Plasma Membrane Profiling Reveals an Essential Role for gp96 in the Cell Surface Expression of LDLR Family Members, Including the LDL Receptor and LRP6. J. Proteome Res. 120207132049008.
Start Year 2010
 
Description structural study of gal8 and ndp52 
Organisation University of Science and Technology of China USTC
Department Hefei National Laboratory for Physical Sciences at the Microscale
Country China 
Sector Charity/Non Profit 
PI Contribution role of gal8 and ndp52 in anti-bacterial defence
Collaborator Contribution structural studies
Impact Li, S., Wandel, M.P., Li, F., Liu, Z., He, C., Wu, J., Shi, Y., and Randow, F. (2013). Sterical hindrance promotes selectivity of the autophagy cargo receptor NDP52 for the danger receptor galectin-8 in antibacterial autophagy. Science Signaling 6, ra9.
Start Year 2013
 
Description ubiquitin in innate immunity 
Organisation Goethe University Frankfurt
Department Institute of Biochemistry
Country Germany 
Sector Academic/University 
PI Contribution expertise in innate immune signalling
Collaborator Contribution expertise in ubiquitin biology
Impact Bloor, S., Ryzhakov, G., Wagner, S., Butler, P. J., Smith, D. L., Krumbach, R., Dikic, I., and Randow, F. (2008). Signal processing by its coil zipper domain activates IKKgamma. Proc Natl Acad Sci U S A 105, 1279-1284. Rahighi, S., Ikeda, F., Kawasaki, M., Akutsu, M., Suzuki, N., Kato, R., Kensche, T., Uejima, T., Bloor, S., Komander, D., Randow, F., Wakatsuki, S., Dikic, I. (2009). Specific Recognition of Linear Ubiquitin Chains by NEMO Is Important for NF-kB Activation. Cell, 1098-1109.
Start Year 2007
 
Description viruses, inflammation and NFkB 
Organisation Flanders Institute for Biotechnology
Country Belgium 
Sector Charity/Non Profit 
PI Contribution expertise in inflammation & signalling
Collaborator Contribution experimental support
Impact Bloor S, Maelfait J, Krumbach R, Beyaert R, Randow F. (2010) Endoplasmic reticulum chaperone gp96 is essential for infection with vesicular stomatitis virus. Proc Natl Acad Sci U S A 107, 6970-5.
Start Year 2008
 
Title screening method 
Description screening method 
IP Reference US2009275635 
Protection Patent granted
Year Protection Granted 2009
Licensed No
Impact No subsequent impact
 
Description LMB Open day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Over 2000 members of the public attended the Open Day who were taken on tours of labs, heard about our science and took part in science activities. Members of my group assisted with supervising the activities.

Requests from the attendees for similar events in future.
Year(s) Of Engagement Activity 2013