Understanding how the brain recovers from cerebral malaria

Cerebral malaria (CM) is a devastating complication of malaria that is responsible for the death and disability of hundreds of thousands of children, each year. At present there is no specific treatment for CM other than anti-malarial drugs, which is a sub-optimal treatment with limited effectiveness that fails to prevent death or disability in a high proportion of sufferers. Indeed, currently 20% of individuals die of CM and 15-30% of survivors exhibit severe long-lasting neurological complications. Critically, in recent years progress towards reducing the incidence of malaria has stalled and there are increasing concerns regarding the development and spread of drug-resistant parasites in different parts of the world. Therefore, new therapies to reduce the health and socio-economic impact of CM, which generally affects vulnerable communities in developing Sub-Saharan countries, are urgently needed.

During CM, blood-derived fluid leaks into the brain, which causes the brain to swell. This leads to raised intracranial pressure, which can be fatal, or which can lead to structural damage to the brain that causes long lasting brain damage in survivors. Moreover, the uncontrolled entry of blood-derived fluid into the brain during CM carries noxious parasitic and host immunological materials into the sensitive cerebral tissue, which causes significant brain inflammation. The subsequent loss of the tightly regulated and balanced brain environment leads to impaired brain functionality and serious neurological disturbances. Thus, the recovery from CM depends upon how quickly fluid and blood-derived materials are drained from the brain of sufferers, and how rapidly the brain tissue can be cleansed, to reestablish the necessary healthy brain environment. At present we do not know how these events are coordinated.

In this application we plan to use an experimental murine model of CM, which we have extensively validated, combined with a variety of complementary neuroimaging techniques, to identify the specific pathways through which fluid and molecules are drained from the brain during recovery from CM. In objective 1 of this application, we will directly address the routes that fluid and materials exit the brain following anti-malarial drug treatment of CM and we will assess whether these routes are compromised by CM, influencing the speed and efficiency through which the brain can recover from the syndrome. We will employ various techniques to positively and negatively influence the pathways of brain drainage during recovery from CM to identify if therapeutic targeting of these processes are potential new therapies for the CM syndrome.

As the blood-derived fluid is drained from the brain during recovery from CM, other blood-derived materials and waste must be actively pushed from the brain to fully reestablish brain health. Thus, in objective 2 we will assess how the routes that remove fluid and molecules from the brain during recovery from CM are interlinked with the processes that cleanse the brain to return it to health. Specifically, we will address how cerebrospinal fluid is perfused through the brain tissue during recovery from CM and how this is required to dampen brain inflammation, re-establish neuronal signaling, and to regain brain function.

The completion of this project will lead to a step change in our understanding of the processes that control the recovery of the brain following CM, and will reveal new potential therapies for the devasting condition. Importantly, the routes of brain drainage, and how they are regulated and impacted by disease, is currently a major area of research for other brain conditions, such as Alzheimer's disease, stroke and traumatic brain injury. Therefore, the results from this project will have impact beyond the malaria community and will have major relevance for the wider neuroscience community, and our understanding of how to treat brain diseases.

Technical Summary
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. Thus, there is increasing recognition that the successful recovery from CM depends upon the rate and effectiveness of oedematous fluid removal from the brain. However, the pathways that control vasogenic oedema clearance during the recovery from CM remain unknown. Moreover, the physiologic systems that ultimately cleanse the brain tissue of noxious blood-derived products concomitant with removal of vasogenic oedema to return the brain to immunological homeostasis during resolution of CM have yet to be addressed. In this project, we will use a murine model of CM (experimental cerebral malaria; ECM), which we have validated, and use interdisciplinary combinations of dynamic brain imaging (MRI and SPECT-CT), quantitative microscopy (stereomicroscopy, tissue clearing and 3D reconstruction, and confocal), and compartmental tracer injections, to identify and mechanistically test the routes that fluid and blood-derived products are drained from the brain during recovery from CM. We will subsequently identify how fluid and macromolecule efflux is interconnected with the influx of CSF into the brain tissue during recovery from ECM, and how CSF influx is essential to clean the brain tissue and reestablish brain function and ameliorate neuroinflammation during recovery from ECM. Our results will transform our understanding of how the brain recovers from CM, identifying new therapies for this devastating syndrome.