RT Journal Article SR Electronic T1 Brain endothelial STING1 activation by Plasmodium-sequestered heme promotes cerebral malaria via type I IFN response JF bioRxiv FD Cold Spring Harbor Laboratory SP 2022.02.14.480268 DO 10.1101/2022.02.14.480268 A1 Pais, Teresa F. A1 Ali, Hajrabibi A1 Moreira da Silva, Joana A1 Duarte, Nádia A1 Neres, Rita A1 Chhatbar, Chintan A1 Acúrcio, Rita C. A1 Guedes, Rita C. A1 Moraes, Maria Carolina Strano A1 Silva, Bruno Costa A1 Kalinke, Ulrich A1 Penha-Gonçalves, Carlos YR 2022 UL http://biorxiv.org/content/early/2022/04/12/2022.02.14.480268.abstract AB 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 (Pba). This STING1/IFNβ-mediated response increases brain CXCL10 governing the extent of brain leucocyte 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 are significantly protected from CM lethality. Moreover, extracellular particles (EPs) released from Pba-infected erythrocytes activated 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 STING1/IFNβ/CXCL10 axis crucial to CM pathogenesis and lethality.Significance CM results from loss of blood-brain endothelial barrier function caused by unrestrained inflammatory response in the natural course of infection by Plasmodium parasites. However, the role of brain endothelium in triggering inflammatory mechanisms is still undetermined. We found that the innate immune sensor STING1 is crucial for production of IFNβ in brain endothelial cells in Plasmodium-infected mice. This in turn stimulates CXCL10-mediated recruitment of leukocytes and subsequent brain inflammation and tissue damage. We identified within extracellular particles released from Plasmodium-infected erythrocytes, a fraction containing products of hemoglobin degradation, namely heme, which we show can bind STING1. Our results unravel a new angle of CM pathogenesis: heme contained in particles triggers the STING/IFNβ/CXCL10 axis in brain endothelial cells.Competing Interest StatementThe authors have declared no competing interest.