Last Updated

09 Jun 2023

Acute brain injury and blood-brain barrier dysfunction in cerebral malaria (ABC)


To investigate neuronal injury and examine interactions between factors involved in CM pathogenesis and biomarkers of brain injury using the multicellular BBB model.

Principal Investigator
Rationale and Abstract

Cerebral malaria (CM) is an acute neurologic complication of infection with Plasmodium falciparum malaria that presents clinically as an unarousable coma. In CM, several pathogenic mechanisms interact to cause the characteristic neurocognitive sequelae observed in a quarter of surviving children. Infected erythrocytes sequester in the brain microvasculature leading to widespread inflammation, endothelial activation, hypoxic/ischemic injury, glucose abnormalities, hemolysis and cellular injury, resulting blood-brain barrier (BBB) dysfunction, which may interact to cause brain injury. We have found that elevated tau and other markers of injury to neurons are elevated in blood circulation and associated persistent neurodisability in survivors of CM. Further, these brain injury markers are associated with factors involved in the pathogenesis of CM, including glucose abnormalities, cellular injury, and endothelial/BBB dysfunction. What remains unclear is how intraerythrocytic parasites confined within the vascular space, cause injury to neurons without crossing the BBB. Thus, there is a critical need for mechanistic studies to define interactions between factors involved in the pathogenesis of CM leading to BBB dysfunction and neuronal injury. Animal and in-vitro BBB models have been key in advancing our knowledge of CM pathogenesis but limitations of existing models include: 1) interspecies variability of non-falciparum animal models, 2) use of endothelial monolayers that lack key components of the brain parenchyma, 3) reliance on immortalized or primary brain microvascular endothelial cell (BMECs) that lack physiologically relevant barrier properties and/or suffer from batch-to-batch variability. To overcome these limitations, a multicellular BBB model comprised of human-derived BMECs, neurons, and astrocytes has been developed. And the project will validate the brain injury biomarker data in a follow-up cohort of children with CM tested for cognitive impairments at 12- months. The hypothesis is that the sequestration of IEs to BMECs results in BBB dysfunction and the subsequent decrease of glucose availability and release of cellular injury marker lactate dehydrogenase (LDH) causing neuronal injury, which is a predictor of persistent neurodisability in clinical CM. The hypotheses will be tested by the following specific aims: 1) evaluation of the impact of glucose deprivation, cellular injury, and endothelial dysfunction on neuronal injury in an in vitro human-derived multicellular BBB model, and 2) evaluation of a panel of brain injury biomarkers as predictors of neurodisability in clinical CM. Upon completion, this work will establish the human-derived multicellular BBB model as the standard for investigating mechanisms underlying neuronal injury, which have been shown to be a predictor of persistent neurodisability in clinical CM. This model has the potential to transform the field of in-vitro CM neuropathology by facilitating research into new therapeutic targets to prevent or reduce future neurodisability after pediatric CM.

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2022 Feb - 2024 Jan

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