Cerebral malaria (CM) is a life-threatening form of Plasmodium falciparum infection caused by brain inflammation. Brain endothelium dysfunction is a hallmark of CM pathology, which is also associated with the activation of the type I interferon (IFN) inflammatory pathway. The molecular triggers and sensors eliciting brain type I IFN cellular responses during CM remain largely unknown. We herein identified the stimulator of interferon response cGAMP interactor 1 (STING1) as the key innate immune sensor that induces Ifnβ1 transcription in the brain of mice infected with Plasmodium berghei ANKA ( Pba ). This STING1/IFNβ-mediated response increases brain CXCL10 governing the extent of brain leukocyte infiltration and blood–brain barrier (BBB) breakdown, and determining CM lethality. The critical role of brain endothelial cells (BECs) in fueling type I IFN–driven brain inflammation was demonstrated in brain endothelial–specific IFNβ-reporter and STING1-deficient Pba -infected mice, which were significantly protected from CM lethality. Moreover, extracellular particles (EPs) released from Pba -infected erythrocytes activated the STING1-dependent type I IFN response in BECs, a response requiring intracellular acidification. Fractionation of the EPs enabled us to identify a defined fraction carrying hemoglobin degradation remnants that activates STING1/IFNβ in the brain endothelium, a process correlated with heme content. Notably, stimulation of STING1-deficient BECs with heme, docking experiments, and in vitro binding assays unveiled that heme is a putative STING1 ligand. This work shows that heme resultant from the parasite heterotrophic activity operates as an alarmin, triggering brain endothelial inflammatory responses via the STING1/IFNβ/CXCL10 axis crucial to CM pathogenesis and lethality.
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.
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