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Cambridge Immunology Network

 

Research

Host recognition of infection

We use multidisciplinary approaches to understand how bacteria are detected by the host (through Pattern Recognition Receptors (PRRs)), but we are also studying how PRR recognition of allergen proteins or toxic proteins produced by patients link to chronic inflammatory diseases such as allergies and Alzheimer’s disease.  The host has many Pattern Recognition Receptors (PRRs), such as Toll-like receptors (TLRs) and Nod-like receptors (NLRs), that detect bacteria, such as Salmonella entericia serovar Typhimurium, and their associated molecules (such as endotoxin).   We are studying which PRRs detect S. Typhimurium to drive an adaptive immune responses focussing on the NLRs and their effector mechanisms. We work with Pietro Cicuta (Physics) and Julia Gog (DAMPT) to study bacterial interactions with cells and respiratory tissues using mathematical modelling, optical tweezers and real-time imaging.

We are studying the molecular mechanisms underlying how ligands, such as endotoxin, interact with TLR4/MD2 receptor complex to recruit their adaptor signalling molecules, such as Mal and Tram, to initiate intracellular signalling (in collaboration with Nick Gay, Biochemistry). We are using FRET analysis and single molecule florescence techniques to study how TLRs form active signalling protein complexes and recruit adaptor proteins in real-time in live cells (in collaboration with David Klenerman, Chemistry).  Allergens, such as the cat dander protein Fel D1, are readily contaminated by endotoxin and this allows them to be detected by TLR4.  Prevention of host detection may prevent the onset of an allergic response. In particular we are interested in how allergens, such as the cat dander protein Fel d1 enhances TLR4 signalling and whether we can design inhibitors to prevent allergen recognition. Similarly other “toxic” proteins (amyloid beta and alpha synuclein) produced during diseases such as Alzheimer’s and Parkinson’s (respectively) can be recognised by TLR4 to induce inflammation and our research with David Klenerman to understand the molecular basis by which host recognition of these proteins occurs may lead to new treatments for these neuroinflammatory diseases.

 

External collaborations

Successful collaborations with academia and industry underpins all our research.  We collaborate closely with academics in the USA, Europe and Australia to stay at the cutting edge of inflammation and infection research.  A vital part of our research is to forge, and maintain, strong collaborations with the pharmaceutical industry to translate our research into medicines.  We have close links to Genentech (Clare was a visiting professor there in 2016 and 2017) and we have an ongoing collaborative research program with Vishva Dixit’s research group.  Clare is currently on secondment at GSK in Stevenage as part of their Immunology Catalyst program to forge stronger links with academia.  Clare and David Klenerman also have a drug discovery program with Apollo Therapeutics (a collaboration of Cambridge, UCL, Johnson and Johnson, Astra Zeneca and GSK) looking for novel small molecule antagonists against TLR4 as potential treatments for Alzheimer’s disease and asthma.  Clare has had collaborative grants with Zoetis Animal Health, GSK and Astra Zeneca and she currently consults for a number of biotech companies in the UK and the USA.

 

 

Publications

Key publications: 
  1. Pizzuto M, Lonez C, Baroja-Mazo A, Martínez-Banaclocha H, Tourlomousis P, Gangloff M, Pelegrin P, Ruysschaert JM, Gay NJ, Bryant CE. (2019) Saturation of acyl chains converts cardiolipin from an antagonist to an activator of Toll-like receptor-4.  Cell Mol Life Sci. 76:3667-3678. doi: 10.1007/s00018-019-03113-5.
  2. Different soluble aggregates of Aβ42 can give rise to cellular toxicity through different mechanisms.  (2019) De S, Wirthensohn DC, Flagmeier P, Hughes C, Aprile FA, Ruggeri FS, Whiten DR, Emin D, Xia Z, Varela JA, Sormanni P, Kundel F, Knowles TPJ, Dobson CM, Bryant C, Vendruscolo M, Klenerman D.  Nat Commun. 10:1541. doi: 10.1038/s41467-019-09477-3.
  3. De S, Whiten DR, Ruggeri FS, Hughes C, Rodrigues M, Sideris DI, Taylor CG, Aprile FA, Muyldermans S, Knowles TPJ, Vendruscolo M, Bryant C, Blennow K, Skoog I, Kern S, Zetterberg H, Klenerman D. (2019) Soluble aggregates present in cerebrospinal fluid change in size and mechanism of toxicity during Alzheimer's disease progression.  Acta Neuropathol Commun. 7:120. doi: 10.1186/s40478-019-0777-4
  4. Hinz C, Liggi S, Mocciaro G, Jung S, Induruwa I, Pereira M, Bryant CE, Meckelmann SW, O'Donnell VB, Farndale RW, Fjeldsted J, Griffin JL.  (2019) A Comprehensive UHPLC Ion Mobility Quadrupole Time-of-Flight Method for Profiling and Quantification of Eicosanoids, Other Oxylipins, and Fatty Acids.  Anal Chem. 91:8025-8035. doi: 10.1021/acs.analchem.8b04615.
  5. Castro-Dopico T, Dennison TW, Ferdinand JR, Mathews RJ, Fleming A, Clift D, Stewart BJ, Jing C, Strongili K, Labzin LI, Monk EJM, Saeb-Parsy K, Bryant CE, Clare S, Parkes M, Clatworthy MR.  Anti-commensal IgG Drives Intestinal Inflammation and Type 17 Immunity in Ulcerative Colitis. (2019)  Immunity. In press pii: doi: 10.1016/j.immuni.2019.02.006
  6. Hughes CD, Choi ML, Ryten M, Hopkins L, Drews A, Botía JA, Iljina M, Rodrigues M, Gagliano SA, Gandhi S, Bryant C, Klenerman D. Picomolar concentrations of oligomeric alpha-synuclein sensitizes TLR4 to play an initiating role in Parkinson's disease pathogenesis. (2019) Acta Neuropathol. 137, 103-120. doi: 10.1007/s00401-018-1907-y.
  7. Latty SL, Sakai J, Hopkins L, Verstak B, Paramo T, Berglund NA, Cammorota E, Cicuta PC, Gay NJ, Bond PJ, Klenerman D, Bryant CE (2018) Activation of Toll-like receptors nucleates assembly of the MyDDosome signaling hub ELife pii: e31377. doi: 10.7554/eLife.31377. Faculty1000prime
  8. Wang L, Keatch R, Zhao Q, Wright JA, Bryant CE, Redmann AL, Terentjev EM. (2018) Influence of type-I fimbriae and fluid shear stress on bacterial behavior and multicellular architecture of early Escherichia coli biofilms at single-cell resolution.  Appl Environ Microbiol. pii: AEM.02343-17. doi: 10.1128/AEM.02343-17
  9. Ritchie L, Tate R, Chamberlain LH, Robertson G, Zagnoni M, Sposito T, Wray S, Wright JA, Bryant CE, Gay NJ, Bushell TJ (2018) Toll-like receptor 3 activation impairs excitability and synaptic activity via TRIF signalling in immature rat and human neurons. J Neuropharm. 135:1-10. doi: 10.1016/j.neuropharm.2018.02.025
  10. Iljina M, Hong L, Horrocks MH, Ludtmann MH, Choi ML, Hughes CD, Ruggeri FS, Guilliams T, Buell AK, Lee JE, Gandhi S, Lee SF, Bryant CE, Vendruscolo M, Knowles TPJ, Dobson CM, De Genst E, Klenerman D. (2017) Nanobodies raised against monomeric -synuclein inhibit fibril formation and destabilize toxic oligomeric species.  BMC Biol. 15:57. doi: 10.1186/s12915-017-0390-6.
  11. Feriani L, Juenet M, Fowler CJ, Bruot N, Chioccioli M, Holland SM, Bryant CE, Cicuta P. (2017) Assessing the Collective Dynamics of Motile Cilia in Cultures of Human Airway Cells by Multiscale DDM.  Biophys J. 113:109-119. doi: 10.1016/j.bpj.2017.05.028.
  12. Sakai J, Cammarota E, Wright JA, Cicuta P, Gottschalk RA, Li N, Fraser IDC, Bryant CE (2017) Lipopolysaccharide-induced NF-B nuclear translocation is primarily dependent on MyD88, but TNFα expression requires TRIF and MyD88.  Sci Rep. 7:1428. doi: 10.1038/s41598-017-01600-y.
  13. Iljina M, Tosatto L, Choi ML, Sang JC, Ye Y, Hughes CD, Bryant CE, Gandhi S, Klenerman D. (2016) Arachidonic acid mediates the formation of abundant alpha-helical multimers of alpha-synuclein. Sci Rep. 27;6:33928.
  14. Dossang AC, Motshwene PG, Yang Y, Symmons MF, Bryant CE, Borman S, George J, Weber AN, Gay NJ. (2016) The N-terminal loop of IRAK-4 death domain regulates ordered assembly of the Myddosome signalling scaffold.  Sci Rep. 6:37267
  15. Pereira, M., Tourlomousis, P., Wright, J.A., Monie, T.P., Bryant, CE (2016) CARD9 negatively regulates NLRP3-induced IL-1β production upon Salmonella infection of macrophages.  Nature Communications 7:12874. doi: 10.1038/ncomms12874
  16. Saint RJ, D'Elia RV, Bryant C, Clark GC, Atkins HS (2016)  Mitogen-activated protein kinases (MAPKs) are modulated during Francisella tularensis infection, but inhibition of extracellular-signal-regulated kinases (ERKs) is of limited therapeutic benefit. Eur J Clin Microbiol Infect Dis.
  17. Mills EL, Kelly B, Logan A, Costa AS, Varma M, Bryant CE, Tourlomousis P, Däbritz JH, Gottlieb E, Latorre I, Corr SC, McManus G, Ryan D, Jacobs HT, Szibor M, Xavier RJ, Braun T, Frezza C, Murphy MP, O'Neill LA (2016)  Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages. Cell. 2016 pii: S0092-8674(16)31162-X. doi: 10.1016/j.cell.2016.08.064.
  18. Iljina M, Tosatto L, Choi ML, Sang JC, Ye Y, Hughes CD, Bryant CE, Gandhi S, Klenerman D. (2016) Arachidonic acid mediates the formation of abundant alpha-helical multimers of alpha-synuclein.  Sci Rep. 6:33928. doi: 10.1038/srep33928.
  19. Falcone EL, Abusleme L, Swamydas M, Lionakis MS, Ding L, Hsu AP, Zelazny AM, Moutsopoulos NM, Kuhns DB, Deming C, Quiñones M, Segre JA, Bryant CE, Holland SM.  (2016) Colitis susceptibility in p47(phox-/-) mice is mediated by the microbiome.  Microbiome. 4:13 doi: 10.1186/s40168-016-0159-0.
  20. Patin EC, Jones AV, Thompson A, Clement M, Liao CT, Griffiths JS, Wallace LE, Bryant CE, Lang R, Rosenstiel P, Humphreys IR, Taylor PR, Jones GW, Orr SJ. (2016) IL-27 Induced by Select Candida spp. via TLR7/NOD2 Signaling and IFN-β Production Inhibits Fungal Clearance. J Immunol. 197:208-21.
  21. Paramo T, Tomasio SM, Irvine KL, Bryant CE, Bond PJ. (2015) Energetics of Endotoxin Recognition in the Toll-Like Receptor 4 Innate Immune Response.  Sci Rep. 5:17997.
  22. Lonez C, Irvine KL, Pizzuto M, Schmidt BI, Gay NJ, Ruysschaert JM, Gangloff M, Bryant CE.  (2015)  Critical residues involved in Toll-like receptor 4 activation by cationic lipid nanocarriers are not located at the lipopolysaccharide-binding interface.  Cell Mol Life Sci., 72: 3971-82
  23. Jabir MS, Hopkins L, Ritchie ND, Ullah I, Bayes HK, Li D, Tourlomousis P, Lupton A, Puleston D, Simon AK, Bryant C, Evans TJ. (2015)  Mitochondrial damage contributes to Pseudomonas aeruginosa activation of the inflammasome and is downregulated by autophagy. Autophagy 11:166-82.
  24. Achouri S, Wright JA, Evans L, Macleod C, Fraser G, Cicuta P, Bryant CE.  The frequency and duration of Salmonella-macrophage adhesion events determines infection efficiency. 2015 Philos Trans R Soc Lond B Biol Sci. 370:20140033
  25. Man SM, Ekpenyong A, Tourlomousis P, Achouri S, Cammarota E, Hughes K, Rizzo A, Ng G, Wright JA, Cicuta P, Guck JR, Bryant CE.  (2014) Actin polymerization as a key innate immune effector mechanism to control Salmonella infection. Proc Natl Acad Sci. 111:17588-93
  26. Hepburn L, Prajsnar TK, Klapholz C, Moreno P, Loynes CA, Ogryzko NV, Brown K, Schiebler M, Hegyi K, Antrobus R, Hammond KL, Connolly J, Ochoa B, Bryant C, Otto M, Surewaard B, Seneviratne SL, Grogono DM, Cachat J, Ny T, Kaser A, Török ME, Peacock SJ, Holden M, Blundell T, Wang L, Ligoxygakis P, Minichiello L, Woods CG, Foster SJ, Renshaw SA, Floto RA. (2014) A Spaetzle-like role for nerve growth factor β in vertebrate immunity to Staphylococcus aureus.  Science. 346:641-6.
  27. Hold GL, Berry S, Saunders KA, Drew J, Mayer C, Brookes H, Gay NJ, El-Omar EM, Bryant CE.  (2014) The TLR4 D299G and T399I SNPs Are Constitutively Active to Up-Regulate Expression of Trif-Dependent Genes.  PLoS One. 9:e111460
  28. Irvine KL, Gangloff M, Walsh CM, Spring DR, Gay NJ, Bryant CE. (2014).  Identification of key residues that confer Rhodobacter sphaeroides LPS activity at horse TLR4/MD-2.  PLoS One.  9:e98776  
  29. Liaunardy-Jopeace A, Bryant CE, Gay NJ. (2014) The COP II adaptor protein TMED7 is required to initiate and mediate the delivery of TLR4 to the plasma membrane. Sci Signal.  7(336):ra70
  30. Man, S.M., Hopkins, L.J., Nugent, E., Cox, S., Glück, I., Tourlomousis, P., Wright, J.A., Cicuta, P., Monie, T.P. and Bryant, C.E.  (2014)  Inflammasome activation causes dual recruitment of NLRC4 and NLRP3 to the same macro-molecular complex. Proc Natl Acad Sci 111, 7403-8          
  31. Jabir MS, Ritchie ND, Li D, Bayes HK, Tourlomousis P, Puleston D, Lupton A, Hopkins L, Simon AK, Bryant C, Evans TJ.  (2014) Caspase-1 cleavage of the TLR adaptor TRIF inhibits autophagy and β-interferon production during Pseudomonas aeruginosa infection.  Cell Host Microbe. 15, 214-27
  32. Herre J, Grönlund H, Brooks H, Hopkins L, Waggoner L, Murton B, Gangloff M, Opaleye O, Chilvers ER, Fitzgerald K, Gay N, Monie T, Bryant C.  Allergens as Immunomodulatory Proteins: The Cat Dander Protein Fel d 1 Enhances TLR Activation by Lipid Ligands. J Immunol. 2013 Aug 15;191(4):1529-35.
  33. Bryant CE, Monie TP. Mice, men and the relatives: cross-species studies underpin innate immunity. Open Biol. 2012 Apr;2(4):120015.
  34. Gog JR, Murcia A, Osterman N, Restif O, McKinley TJ, Sheppard M, Achouri S, Wei B, Mastroeni P, Wood JL, Maskell DJ, Cicuta P, Bryant CE. Dynamics of Salmonella infection of macrophages at the single cell level. J R Soc Interface. 2012 Oct 7;9(75):2696-707
  35. Smyth T, Tötemeyer S, Haugland S, Willers C, Peters S, Maskell D, and Bryant CE, (2008) Dexamethasone modulates Salmonella entericia serovar Typhimurium infection in vivo independently of the glucocorticoid-inducible protein annexin 1, FEMS Immunol. Micro. (In press; available on line).
  36. Núñez Miguel R, Wong J, Westoll JF, Brooks HJ, O’Neill LAJ, Gay NJ, Bryant CE, and Monie TP, (2007) A Dimer of the Toll-Like Receptor 4 Cytoplasmic Domain Provides a Specific Scaffold for the Recruitment of Signalling Adaptor Proteins. PLoS One 2, e788.
  37. Tötemeyer S, Sheppard S, Lloyd A, Roper D, Dowson C, Underhill D, Murray P, Maskell D, Bryant, C.E (2006) Interferon-gamma enhances production of nitric oxide from macrophages via a mechanism that depends on NOD 2, J. Immunol. 176, 4804–10
  38. Tötemeyer S, Kaiser P, Maskell DJ, Bryant CE, (2005) Sublethal infection of C57BL/6 mice with Salmonella enterica serovar Typhimurium leads to an increase in levels of Toll-like receptor 1 (TLR1), TLR2, and TLR9 mRNA as well as a decrease in levels of TLR6 mRNA in infected organs. Infect. Immun. 73,1873–8         

 

Invited Reviews

  1. Gram AM, Booty LM, Bryant CE.  Chopping GSDMD: caspase-8 has joined the team of pyroptosis-mediating caspases.  (2019) EMBO J. 38 pii: e102065. doi: 10.15252/embj.2019102065.
  2. Kufer TA, Creagh EM, Bryant CE. (2019) Guardians of the Cell: Effector-Triggered Immunity Steers Mammalian Immune Defense.  Trends Immunol. pii: S1471-4906(19)30168-1. doi: 10.1016/j.it.2019.08.001.
  3. Macleod C, Bryant CE. (2017) Visualising pattern recognition receptor signalling. Biochem Soc Trans. 45:1077-1085. doi: 10.1042/BST20160459. 
  4. Patel MN, Carroll RG, Galván-Peña S, Mills EL, Olden R, Triantafilou M, Wolf AI, Bryant CE, Triantafilou K, Masters SL (2017) Inflammasome Priming in Sterile Inflammatory Disease. Trends Mol Med 23:165-180.doi: 10.1016/j.molmed.2016.12.007.
  5. Wright JA, Bryant CE. The killer protein Gasdermin D.  (2016) Cell Death Differ. doi: 10.1038/cdd.2016.100.
  6. Monie TP, Bryant CE.  Caspase-8 functions as a key mediator of inflammation and pro-IL-1β processing via both canonical and non-canonical pathways.  Immunol Rev. 2015, 265:181-93.
  7. Bryant, C.E., Orr, S., Ferguson, B., Symmons, M.F., Boyle, J.P. and Monie, T.P. (2015) International Union of Basic and Clinical Pharmacology. XCVI. Pattern Recognition Receptors in Health and Disease.  Pharmacol. Rev. 67:462–504
  8. Gay NJ, Symmons MF, Gangloff M, Bryant CE. (2014) Assembly and localization of Toll-like receptor signalling complexes.  Nat Rev Immunol. 14:546-58.
  9. Bryant CE, Symmons M, Gay NJ. (2014) Toll-like receptor signalling through macromolecular protein complexes.  Mol Immunol. pii: S0161-5890(14)00164-3.

Other Professional Activities

Public Involvement/Engagement

Professor Bryant is involved with the Cambridge Science Festival, and chairs a very popular panel discussion meeting where researchers from the Cambridge Immunology Network engage with the public on an Immunology related topics.

She also contributes to science communication and has had several articles published with The Naked Scientists, which is one of the world's most popular science shows based at Cambridge University:

 

Professor Clare  Bryant
Takes PhD students
Available for consultancy

Affiliations

Person keywords: 
cytosis
NOD-like receptors Toll-like receptors
allergy
protein purification
immunoprecipitation
cell culture
confocal microscopy
interleukin
cytokines
reporter assays
bacteria
inflammation
monocytes
immunohistochemistry
macrophages
infection
animal models
inflammasome,
pattern recognition receptors
nitric oxide
eicosanoids
adjuvants
mutagenesis
signal transduction
innate immunity
microscopy
fluorescence microscopy
signalling
dendritic cells
cloning

Automatic single cell image analysis to measure the translocation of the pro-inflammatory transcription factor Nuclear Factor kappa B into the nucleus and the accompanying expression of the cytokine tumor necrosis factor alpha over time after stimulation of cells with lipopolysaccharide. Macrophages are transduced to express green fluorescent protein-Rel A (a constituent of Nuclear Factor kappa B) and a tumor necrosis factor alpha promoter linked to mCherry (red)