Title: Unravelling Inflammatory Caspases Co-regulation
Funder: The Academy of Medical Sciences

Abstract: The innate immune is the body first line of defence against pathogens. One key pathway of the innate immune system, called the inflammasome, activates signalling proteases named inflammatory caspases. Inflammatory caspases are cleaving important proteins in the cells to orchestrate the innate immune responses and protect the body. However, dysregulation of caspases activity is harmful and leads to various immune conditions like sepsis, rheumatoid arthritis, and gout and have been involved in other conditions with inflammatory components like diabetes and ageing. Humans have three inflammatory caspases, caspase-1, -4 and -5. The canonical inflammasome activates caspase-1 whereas by the non-canonical inflammasome activates caspase-4 and -5. Despite their crucial roles in innate immunity, inflammatory caspases regulatory mechanism are poorly described. Here, we will study how human inflammatory caspases activity is regulated and how two inflammatory caspases, caspase-1 and -4, fine-tuned each other activity to impact immune responses. Our exciting preliminary data suggest that caspase-4 can be activated on the canonical inflammasome, challenging the current dogma. Using a combination of cell biology and biochemical approaches, we aim to understand how caspase-1 and 4 regulate each other during human immune responses. Ultimately, the fundamental knowledge gain through this project will guide the development of caspase inhibitors for inflammasome-related diseases.

Lay abstract: Your innate immune cells are your first line of defence against pathogens. During bacterial infection, immune cells like macrophages have developed mechanisms to alert your body to the presence of an intruder and to enable its elimination. One of these mechanisms is called the inflammasome. Inflammasomes activate enzymes called inflammatory caspases that control the production of immune effectors that generate fever and destroy infected cells. Although they are essential to control infections, caspases are involved in many inflammatory diseases. When out of control, caspases cause harmful inflammation that leads to diseases. These include rheumatoid arthritis, Alzheimer’s disease, cancer, and diabetes. Despite their key role in coordinating inflammasome function, we have limited knowledge of how human caspases are regulated during inflammation and infections. Understanding caspase regulation is crucial for the development of novel drugs to treat inflammatory diseases and infections. In this project, I want to understand how two inflammatory caspases, caspase-1 and -4, cooperate to help our body to control infections. My preliminary results suggest that these proteases cleave each other to fine-tune the response to bacterial infection. Using multidisciplinary approaches, I will study how caspases are activated and regulated in humans, providing important knowledge to support the development of therapies against infections and inflammatory diseases, and potentially novel biomarkers to detect inflammasome-associated diseases. This project will position me as an emerging international leader in innate immunity and protease signalling and will open up exciting research avenues to further study caspases in immune diseases and infections.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM