Dissecting how the NLRP3 inflammasome provokes blood brain barrier dysfunction during cerebral malaria

Diseases caused by parasites have devastating consequences on the human population. The most important disease caused by a parasite is malaria which causes over 400,000 deaths every year. One of the most devastating consequences of malaria is a syndrome called cerebral malaria. Cerebral malaria is where the disease has affected the brain. The outcome of cerebral malaria, which is most prevalent in children, is death, caused by swelling of the brain. This swelling occurs because the barrier between the blood and the brain breaks down. The integrity of this 'blood-brain barrier' is critical for normal brain function and survival. Our research has provided good clues to how the blood-brain barrier breaks down in cerebral malaria. The main culprit are our own immune systems that are activated by the disease and turn against our own bodies. A specific part of our immune system, called the 'NLRP3 inflammasome' becomes active to break the blood-brain barrier. If we can understand how, when, and where this happens we will be better able to develop ways of blocking the NLRP3 inflammasome and its effects. If we can do this then we may be better able to treat cerebral malaria, and ultimately prevent the deaths of hundreds of thousands of children every year. Our research may also be relevant to other diseases where the blood-brain barrier is compromised.

Cerebral malaria (CM) is one of the most severe complications of malaria, responsible for hundreds of thousands of deaths, each year. At present the only treatment for CM is anti-malarial drugs, which is a non-specific sub-optimal treatment that fails to prevent death in 20% of cases, with 15-30% of survivors of CM also experiencing long-lasting and life-changing neurological sequela. Brain swelling, due to vasogenic oedema, is a key pathological event in CM that, in severe cases, can cause brain stem herniation and death, or cause structural damage in survivors. Our preliminary data suggest that inflammation caused by the NLRP3 inflammasome is responsible for damaging the integrity of the blood-brain barrier and exacerbating vasogenic oedema. In this project, we will use a murine model of CM (experimental cerebral malaria; ECM), which we have validated, and use a combination of imaging, biochemical, and immunological techniques to determine the temporal and spatial regulation of NLRP3 inflammasome activation, the proximity of this event to areas of blood-brain barrier disruption, and how NLRP3-dependent inflammation signals to affect vasogenic oedema. The full translational relevance of our discoveries in the pre-clinical model will be established in human post-mortem brain tissue from fatal paediatric cerebral malaria. The outcome of this project will be a step-change in our understanding of how the NLRP3 inflammasome controls blood-brain barrier opening during CM and following anti-malarial drug treatment. This work will allow us to identify crucial new adjunct therapies to rapidly limit fluid influx, brain swelling and neuroinflammation, transforming the treatment success of this devastating condition. More broadly, our results will reveal fundamental new insights into how the NLRP3 inflammasome is activated and causes vasculopathy within the brain.