1. Brain endothelial STING1 activation by Plasmodium -sequestered heme promotes cerebral malaria via type I IFN response.
- Author
-
Pais TF, Ali H, Moreira da Silva J, Duarte N, Neres R, Chhatbar C, Acúrcio RC, Guedes RC, Strano Moraes MC, Costa-Silva B, Kalinke U, and Penha-Gonçalves C
- Subjects
- Animals, Endothelial Cells immunology, Endothelial Cells metabolism, Endothelial Cells parasitology, Endothelium immunology, Endothelium parasitology, Mice, Plasmodium berghei metabolism, Transcriptional Activation immunology, Brain parasitology, Heme metabolism, Interferon-beta immunology, Malaria, Cerebral immunology, Malaria, Cerebral parasitology, Membrane Proteins genetics, Membrane Proteins metabolism
- Abstract
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.
- Published
- 2022
- Full Text
- View/download PDF