Brain endothelial STING1 activation by Plasmodium-sequestered heme promotes cerebral malaria via type I IFN response

Abstract

Cerebral malaria (CM), caused by infection with Plasmodium falciparum, is characterized by brain inflammation. Type I IFN inflammatory response underlies CM pathogenesis leading to brain endothelium dysfunction with the loss of blood-brain-barrier (BBB). We identified the stimulator of interferon response cGAMP interactor 1 (STING1) as the key innate immune sensor that activates type I IFN pathway and CXCL10 expression governing brain leukocyte infiltration and CM lethality in mice. Brain endothelial-specific IFNβ-reporter and STING1 KO mice unveiled a critical role of brain endothelial cells (BECs) in fuelling type I IFN-driven inflammation in the brain during malaria infection. We show that extracellular particles (EPs) derived from Plasmodium-infected erythrocytes and containing digestive vacuoles trigger a STING1-dependent IFNβ response in BECs. This response increases with heme content in digestive vacuoles, which directly activates BECs via STING1. Together, our findings uncovered that heme-stimulated endothelial STING1 drives type I IFN response and subsequent brain pathology.