Malaria remains a significant global health challenge and economic burden in 85 countries, with Africa bearing the heaviest impact. In 2022, there were 249 million new cases and 608,000 deaths reported worldwide. Infection is primarily caused by Plasmodium falciparum, which accounts for over 90% of cases and deaths, particularly affecting children under five. These children are especially vulnerable to cerebral malaria, one of the most fatal outcomes of P. falciparum infection. Currently, no vaccine or treatment specifically targets this condition, highlighting the urgent need for innovative tools and interventions.
Cerebral malaria (CM) is characterised by the accumulation of malaria-infected red blood cells in the brain vasculature which lead to vascular blockage, blood flow impairment, brain-blood-barrier inflammation and disfunction leading to brain haemorrhages and swelling.
A major challenge in studying cerebral malaria (CM) is the brain's inaccessibility during active infection. Current knowledge is based largely on autopsies, which do not reflect disease onset or progression. This gap highlights the need for models that capture the complex pathogenesis of CM. Existing in vitro models, such as 2D cultures and flow chambers, lack flow or fail to replicate the vascular tree's multicellular complexity. While brain organoids are promising as 3D models, their heterogeneous architectures and lack of perfusable vasculature limit their use. Furthermore, animal models show minimal intracerebral accumulation, a key feature of human malaria infection.
To overcome these limitations, during my Marie Skłodowska-Curie postdoctoral fellowship in the Bernabeu Lab at EMBL Barcelona, I developed a bioengineered 3D model of human brain microvessels to study the pathogenesis of cerebral malaria (CM). I investigated the binding mechanism between malaria-infected red blood cells and endothelial proteins in the brain microvessels. Specifically, I:
1. Identified antibodies from individuals exposed to malaria that inhibit a specific parasite-host interaction, representing a common mechanism of acquired immunity to CM.
2. Demonstrated that febrile temperatures during malaria infection increase parasite accumulation in the brain microvessels.
3. Designed and fabricated prototypes of a 3D in vitro microvasculatures, serving as preliminary models for developing brain-region-specific microvasculature chips for white matter, grey matter, and the basal ganglia.
