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In vitro brain microvascular model to tackle fever in cerebral malaria

Project description

An in vitro model for studying cerebral malaria

Malaria is a mosquito-borne infectious disease caused by the parasite Plasmodium falciparum. Despite treatment initiation, the parasite may reach the brain and lead to the severe neurological complication of cerebral malaria. Existing evidence indicates that parasite accumulation in the brain leads to vessel occlusion, disruption of the blood–brain barrier and brain swelling. To elucidate the mechanisms of cerebral malaria, the EU-funded FEBRIS project will develop an in vitro model that uses microfluidics and endothelial cells to recapitulate the physiological processes of brain vasculature. Results will provide important insight into the pathogenesis of cerebral malaria and could lead to new therapies.

Objective

Malaria still claims more than 400,000 deaths every year, above all in children under 5. All symptoms are caused by the blood stage of the deadliest parasite species Plasmodium falciparum (Pf), which infects human red blood cells. Cerebral malaria (CM) is the most severe complication, with 20% mortality rate even after administration of fast-acting antimalarials, and is due to build-up of parasites in the brain microvasculature leading to vessel occlusion, blood-brain-barrier disruption, and brain swelling. Current knowledge of CM is based primarily on autopsy analysis, because of limitations of suitable animal models, where disease onset and progression cannot be studied. Additionally, different areas of the brain with distinctive vascular patterns show CM-specific lesions supporting the hypothesis of different regional microcirculations. In my project FEBRIS I will tackle, for the first time, human CM process in vitro models of white and grey matter, and basal ganglia, with cutting-edge bioengineering approaches. I will develop 3D microfluidic devices coated with endothelial cells mimicking vessel networks and physiological flow rates of these three regions of the brain. Numerical simulations will identify critical factors causing blood stagnation, predicting where and when a clog could form. Using this technology brings a unique angle to malaria research to systematically evaluate the unexplored effect of fever on molecular and biophysical mechanisms of Pf sequestration, and the concurrent vascular damage. The obtained findings will be validated with parasites from the field and brain samples from CM patients, examined with pioneer 3D autopsy imaging. This interdisciplinary approach, favoured by my host, aims to provide a holistic understanding of CM pathogenesis. The acquired knowledge could lead to new therapies to reduce fatality by malaria disease and, in a broader context, this innovative platform could be employed to study other neurovascular diseases.

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Coordinator

EUROPEAN MOLECULAR BIOLOGY LABORATORY
Net EU contribution
€ 172 932,48
Address
Meyerhofstrasse 1
69117 Heidelberg
Germany

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Region
Baden-Württemberg Karlsruhe Heidelberg, Stadtkreis
Activity type
Research Organisations
Links
Other funding
€ 0,00