Molecular and cellular mechanisms of innate immunity.

Chronic inflammation plays a central role in many debilitating diseases such as arthritis, sepsis, cancer and Parkinson's disease (PD). The burden of chronic inflammatory diseases is considerable and increasing with 1,000,000 cases and 200,000 deaths from sepsis annually in the United States alone and the incidence of PD is projected to double to about 250,000 in the UK by 2050. Treatments for these conditions generally either provide symptomatic relief (non-steroidal anti-inflammatory drugs) or immunosuppression with very serious side effects.

The Gay Group's research vision is to understand how normal protective immunity is regulated so as to avoid the damaging inflammatory reactions associated with diseases like sepsis. We focus on the signalling receptors that recognise infectious and sterile inflammatory stimuli and the complex regulatory networks that control the signalling responses. Understanding these processes at the molecular level will allow the development of more specific, targeted therapies for inflammatory diseases.

Research objectives

• Elucidate the molecular mechanisms and dynamics of the MyD88 and TRIF scaffolds in Toll-like receptor signal transduction.

• Define the role of pathway crosstalk and phosphoinositide metabolism in inflammatory signalling moderated by BCAP.

• Explore how inflammatory signalling is modified by LRRK2, a kinase associated with Parkinson's disease, and the role of the guanosine exchange factor Rapgef3. To achieve these first three objectives we will use a highly interdisciplinary approach that brings together structural analysis, single molecule imaging, biophysics and cell biology.

• Determine how innate immune activation influences chronic disease in Southerner's American trypanosomiasis.

Key publications

Gay NJ, Symmons MF, Gangloff M, Bryant CE (2014). Assembly and localization of Toll-like receptor signalling complexes. Nat. Rev. Immunol., 14(8):546-558. doi: 10.1038/nri3713

Latty SL, Sakai J, Hopkins L, Verstak B, Paramo T, Berglund NA, Cammarota E, Cicuta P, Gay NJ, Bond PJ, Klenerman D, Bryant CE (2018). Activation of Toll-like receptors nucleates assembly of the MyDDosome signaling hub. eLife, 7:e31377. doi: 10.7554/eLife.31377

Sardinha-Silva A, Mendonça-Natividade FC, Pinzan CF, Lopes CD, Costa DL, Jacot D, Fernandes FF, Zorzetto-Fernandes ALV, Gay NJ, Sher A, Jankovic D, Soldati-Favre D, Grigg ME, Roque-Barreira MC (2019). The lectin-specific activity of Toxoplasma gondii microneme proteins 1 and 4 binds Toll-like receptor 2 and 4 N-glycans to regulate innate immune priming. PLoS Pathog., 15(6):e1007871. doi: 10.1371/journal.ppat.1007871

Moncrieffe MC, Bollschweiler D, Li B, Penczek PA, Hopkins L, Bryant CE, Klenerman D, Gay NJ (2020). MyD88 death-domain oligomerization determines MyDDosome architecture: Implications for Toll-like receptor signaling. Structure, 28(1):1-9. doi: 10.1016/j.str.2020.01.003

Lauenstein JU, Udgata A, Bartram A, De Sutter D, Fisher DI, Halabi S, Eyckerman S, Gay NJ (2019). Phosphorylation of the multifunctional signal transducer B-cell adaptor protein (BCAP) promotes recruitment of multiple SH2/SH3 proteins including GRB2. J. Biol. Chem., 294(52):19852-19861. doi: 10.1074/jbc.RA119.009931