Inflammasome complex organisation in infectious and inflammatory diseases

Inflammation protects people against infections, but it can be over activated, for example in sepsis or sterile inflammation, where it causes severe disease. Sepsis caused 20% of all global deaths in 2017, but the severe disease caused by COVID-19 has markedly increased this death toll. Sterile inflammation underpins diseases such as arthritis, type II diabetes, cancer, chronic respiratory diseases, atherosclerosis, Alzheimer's and Parkinson's diseases with a growing global burden. In the UK over 20 million people live with arthritis and approximately 850,000 people live with dementia costing £26 billion a year with cases forecast to reach 2 million by 2051. Globally 545 million people live with chronic respiratory disease. Development of new drugs for sepsis and for chronic inflammatory conditions are badly needed because the current ones are either not very efficient and/or have nasty side effects. Receptors present inside the cell (NOD-like receptors (NLRs)) sense pathogens or sterile inflammatory stimuli to form a complex called the inflammasome which ultimately kills the cell. Inflammasome complexes are critical for driving inflammation so to develop better anti-inflammatory therapies it is essential to understand how the inflammasome complex is organized within cells which is the aim of this proposal. Here we will study how immune cells form the inflammasome within cells, how it may be disrupted and determine whether there are any consequences for the cell by this disruptive process. By determining the mechanisms by which inflammasomes form in response to bacterial infection and inflammatory stimuli this will help us identify new targets for anti-inflammatory drugs and hence help develop new therapies for many important diseases.

Inflammation protects the host against infectious disease, but when dysregulated, for example in sterile inflammation, it causes severe disease. Sterile inflammation underpins diseases such as arthritis, type II diabetes, cancer, chronic respiratory diseases, atherosclerosis, Alzheimer's and Parkinson's diseases with a growing global burden. Current anti-inflammatory approaches for these diseases are inadequate generally providing either symptomatic relief or immunosuppression so there is an urgent unmet medical need for newer, safer drugs. Inflammasome complexes drive inflammation so to develop better drugs it is essential to understand how the inflammasome complex is organized.
Canonical inflammasomes are multi-protein protein complexes composed of nucleotide oligomerisation domain leucine rich repeat receptors (NLRs), the adaptor protein apoptosis-associated speck-like protein (ASC) and effector caspases (caspase 1). They process the cytokines pro-interleukin 1beta and pro- interleukin 18 to their active forms and cleave the death effector protein gasdermin D to trigger lytic cell death. Inflammasomes can recruit multiple NLRs and effectors (such as caspase 1 and caspase 8) forming signalling platforms that integrate cytokine processing and multiple cell death pathways. It is unclear how inflammasome signalling platforms are organised in the cell yet this information is critical to guide development of interventional strategies. Combining different microscopy techniques (cryo-electron tomography (cryoET), super resolution and single molecule fluorescent approaches) we have uncovered the organisation of ASC and caspase 1 within the cell. Here we will leverage our cutting-edge microscopic analysis combined with mutagenesis and functional analysis to uncover the mechanistic basis of inflammasome formation in response to bacterial infection and inflammatory stimuli and help identify sites for targeted intervention.