Scientists Finger Protein RIPK1 for Brain Vessel Damage in Cerebral Malaria

A team at the Bernhard Nocht Institute for Tropical Medicine (BNITM) and the University Medical Center Hamburg-Eppendorf (UKE), working with international partners, traced how malaria wrecks the brain's smallest blood vessels. Their suspect: RIPK1, a protein that regulates inflammation and cell death. In mice infected with the malaria parasite Plasmodium berghei, gene programs tied to cell death ramped up inside the endothelial cells that line the blood vessels. The study appears in Science Advances.

Malaria killed 610,000 people in 2024 out of more than 280 million cases, according to WHO estimates. Ninety-five percent of those deaths hit sub-Saharan Africa, where children under 5 bear the brunt. Cerebral malaria, the form marked by deep coma, leaves 25% to 30% of surviving children with lasting problems in motor skills, learning or memory. Some patients die even when they get treatment.

The mechanism starts with red blood cells infected by Plasmodium falciparum sticking to vessel walls, choking blood flow. Inflammation flares, clotting falters, the brain swells and small bleeds appear. CD8-positive T cells help drive the vascular damage in mice; when the researchers removed them, the cell death signals in the endothelial cells quieted down. Cross-referencing RNA data from both cell types pointed the finger at RIPK1.

Human evidence backed the mouse work. In brain tissue from eight children in Malawi who died of cerebral malaria, endothelial cells carried stronger signs of activated RIPK1 than tissue from eight people who died of other severe brain diseases. Genetic data from malaria patients also linked variants in programmed-cell-death genes, including the RIPK1 network, to severe malaria. First author Dr. Alexandros Hadjilaou called RIPK1 fascinating because it helps determine whether a cell lives or dies, and under inflammatory conditions its enzymatic activity can push cells toward death.

Two experiments tested whether blocking RIPK1 helps. Mice genetically altered so RIPK1 enzyme activity was silenced in brain endothelial cells lived longer than controls after infection, though the change did not stop death. A second group got GNE684, an experimental compound that acts beyond the cerebral vessels, starting on day one after infection, before neurological symptoms appeared; they also survived longer. Parasite loads in the blood stayed level with the control animals in both groups.

Study leader Dr. Thomas Jacobs said the work identifies RIPK1 as a potential starting point for treatments that complement antiparasitic drugs by protecting the brain. The next step is testing whether giving RIPK1 inhibition later, alongside standard malaria treatment, works and is tolerated.