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 David Klenerman (Chemistry) to study how cells and respiratory tissues respond to infectious and inflammatory insults using mathematical modelling, optical tweezers, super resolution imaging, single molecule imaging and real-time imaging. Importantly we are translating our work to generate new medicines and vaccines for man and animals. We achieve this by different mechanisms including through our own start up companies, collaborating with Biotech companies (such as Apollo Therapeutics and NodThera) and through partnership with big Pharma companies such as Janssen, Astra Zeneca, GSK and Genentech.
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 the 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 so we are working with Apollo Therapeutics to 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 innate immunity research. A vital part of our work 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 was seconded to GSK in Stevenage as part of their Immunology Catalyst program for 3 years 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 different pharmaceutical companies and she currently consults for a number of biotech companies in the UK and the USA.
