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Clare Bryant

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), Julia Gog (DAMPT) and Ray Goldstein (DAMPT) to study bacterial interactions with cells and respiratory tissues using mathematical modelling, optical tweezers and real-time imaging.

RAW 264.7 macrophages expressing the transcription factor RelA-green fluorescent protein (a member of the pro-inflammatory nuclear factor kappa B family of transcription factors) were infected with Salmonella enterica serovar Typhimurium (also expressing green fluorescent protein).  


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.

Key Publications

Clare Bryant

 

Professor Clare Bryant

Professor of Innate Immunity

Wellcome Trust Investigator

Contact details: ceb27@cam.ac.uk

Group members: Dr Lee Hopkins, Dr Panagiotis Tourlomousis

    Plain English

    When infected or injured, our body mounts an inflammatory response to control the infection and repair damaged tissue. Abnormalities with this inflammatory response are associated with diseases such as, diabetes, cancer and  cardiovascular and autoimmune diseases. Understanding how these inflammatory responses are generated may help us find new drugs that fight many diseases of humans and animals. Our research uses specialised microscopy techniques to study how inflammatory responses are formed after activation, by visualizing the different protein constituents associating with each other within the cell. We investigate how different host factors influence how well the inflammatory response is produced. We also study why host responses to bacteria such as Salmonella, which causes severe disease in humans, is much less problematic in other mammals or birds.

    Funding

    Wellcome Trust, BBSRC, MRC, HBLB