Immune congestion drives dural sinus failure and lethal intracranial pressure in cerebral malaria 2308981

Abstract

Abstract Introduction Cerebral malaria (CM) is a severe manifestation of Plasmodium falciparum infection affecting young children and causing hundreds of thousands of deaths each year in Africa. CM progresses rapidly after coma onset, creating a narrow therapeutic window for intervention. Because CM often fails to respond to antimalarial therapy and no adjunctive therapies exist, there is an urgent need to define disease mechanisms and develop fast-acting rescue strategies. Although infected red blood cells in cerebral vasculature were once thought to drive CM by obstructing blood flow, studies in a mouse model revealed a central role for CD8+ T cells in pathogenesis. Our work showed similarities between mice and humans in MRI-defined brain pathology and CD8+ T cell accumulation, supporting development of a therapeutic now in Phase I/IIa trials in African children. Yet it remains unclear how meningeal immune and vascular interactions initiate the rapid neurological decline and lethal intracranial pressure spike characteristic of CM. Methods Here, we combined intravital imaging, electron microscopy, light-sheet imaging, and immunohistochemistry to assess structural and immune cell-mediated changes in the endothelial cells of the dural venous sinuses that drain fluids from the meninges, brain, and skull. Results We identified immune cell-mediated changes in sinus architecture, porosity, vasodilation, and flow that precipitated intracranial pressure (ICP) elevation and death. Notable remodeling of sinus endothelial cell morphology and dynamic behavior occurred before clinical symptom onset, suggesting an early compensatory response to relieve immune congestion and stabilize ICP. As disease progressed, this compensatory capacity was exceeded, leading to abrupt loss of sinus regulation and neurological decline. Conclusion These findings reveal a key neurovascular failure point in CM and highlight a druggable meningeal interface for rapid therapeutic intervention to prevent fatal intracranial pressure crises. Funding Source Intramural research program of the National Institutes of Allergy and Infectious Diseases/NIH Topic Categories Neuroimmunology (NEUR)