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Human derived blood-brain-barrier spheroids to study brain infections

Yvonne Adams

Human brain infections can be caused by a variety of pathogens including bacteria (Borrelia sp. Lyme neuroborreliosis), parasites (Plasmodium falciparum, cerebral malaria) and viruses (Varicella zoster virus – chicken pox). Animal models ranging from mice, rabbits, dogs and monkeys have all been utilised to model how the infections cause disease and interact with the blood-brain-barrier and the immune system. Sadly, none of these animal models accurately represent what happens in the human body.

To address this short coming, the project will utilise a human cell based model of the blood-brain-barrier ; by combining human endothelial cells, astrocytes and pericytes - the components of the blood-brain-barrier - they self-assemble into spheroids. These balls of cells orient themselves with an endothelial layer on the outside, underneath is the pericyte layer, and finally the astrocytes make up the central core of the spheroid. All cells are in direct contact with each other allowing for a more natural interaction, closer to that found in the human body. Using advanced microscopy techniques, it is possible to measure the integrity of the barrier, receptor expression, and gross effects of pathogen exposure. This system also allows for the addition of immune cells, such as macrophages and T cells, to allow for investigations into the transmigration of these cells in response to infection.

This project reduces and replaces the need for animal models, allowing for the rapid investigation of multiple pathogens on human cells. Their ease of use also provides a platform to rapidly screen chemotherapeutics and antibodies for their ability to stop pathogens damaging the blood-brain-barrier, and to determine if they can alleviate the effects of exposure improving treatment and outcomes for patients suffering from these diseases.

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