| First Author | Pais TF | Year | 2022 |
| Journal | Proc Natl Acad Sci U S A | Volume | 119 |
| Issue | 36 | Pages | e2206327119 |
| PubMed ID | 36037380 | Mgi Jnum | J:344199 |
| Mgi Id | MGI:7335935 | Doi | 10.1073/pnas.2206327119 |
| Citation | Pais TF, et al. (2022) Brain endothelial STING1 activation by Plasmodium-sequestered heme promotes cerebral malaria via type I IFN response. Proc Natl Acad Sci U S A 119(36):e2206327119 |
| abstractText | 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 Ifnbeta1 transcription in the brain of mice infected with Plasmodium berghei ANKA (Pba). This STING1/IFNbeta-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 IFNbeta-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/IFNbeta 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/IFNbeta/CXCL10 axis crucial to CM pathogenesis and lethality. |
