Proteolytic control of intracellular lipopolysaccharide signalling

The innate immune system regroups cellular mechanisms that protect your body against infections and tissue damage. One of these mechanisms, the non-canonical inflammasome, is specialised in recognising and responding to a bacterial component called LPS. LPS is at the surface of pathogenic bacteria such as Salmonella, Shigella, and E.coli, which cause gastrointestinal infections.

Inflammasome activate signalling enzymes (protease) called caspases. Caspase activation triggers the release of pro-inflammatory mediators called cytokines, which alert the immune system to clear infections. Inflammasome activation also leads to the death of infected cells, restricting pathogen dissemination.

Inflammasome inhibitors are being developed for various conditions, including infection, sepsis, Alzheimer's, and inflammatory bowel disease. However, the consequences of such inhibitions are poorly defined.

Bacteria have evolved mechanisms to block the non-canonical inflammasome and survive. The immune system has a range of alternative mechanisms that allow responses against such inhibition, but such mechanisms are unknown in the context of the non-canonical inflammasome.

Here, we have identified an exciting novel mechanism, termed CIILR (Caspase-4- independent intracellular LPS response), which occurs upon pharmacological or bacterial inhibition of the non-canonical inflammasomes. We have identified a protein kinase (protein X) controlling this pathway.

Here, we hypothesise that protein X is controlled by caspases and that CIILR is a backup mechanism controlling infections upon inflammasome inhibition. Here, we propose the following aims to explore our hypothesis: AIM1: How is the inflammasome regulating CIILR and protein X? AIM2: What are the consequences of CIILR on infected cells?

AIM3: What are the consequences of CIILS on bacteria?

To do this, we will use a combination of multidisciplinary approaches, including synthetic biology, genome engineering using CRISPR cas9, high-resolution microscopy and cell death assays.

Inflammasomes are essential actors in healthy immune responses. Understanding the consequences of its inhibition is vital for developing better therapy. Therapies targeting the innate immune system and the inflammasomes have emerged as promising for many diseases and as a way to fight antimicrobial resistance.

Therefore, this proposal has the potential to unveil a novel mechanism that will provide critical new knowledge of our innate immune system and novel therapeutic targets to fight infections and inflammatory diseases.