{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T20:23:23Z","timestamp":1772137403970,"version":"3.50.1"},"reference-count":51,"publisher":"Proceedings of the National Academy of Sciences","issue":"36","license":[{"start":{"date-parts":[[2022,8,29]],"date-time":"2022-08-29T00:00:00Z","timestamp":1661731200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,9,6]]},"abstract":"<jats:p>\n                    Cerebral malaria (CM) is a life-threatening form of\n                    <jats:italic>Plasmodium falciparum<\/jats:italic>\n                    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\n                    <jats:italic>Ifn\u03b21<\/jats:italic>\n                    transcription in the brain of mice infected with\n                    <jats:italic>Plasmodium berghei<\/jats:italic>\n                    ANKA (\n                    <jats:italic>Pba<\/jats:italic>\n                    ). This STING1\/IFN\u03b2-mediated response increases brain CXCL10 governing the extent of brain leukocyte infiltration and blood\u2013brain barrier (BBB) breakdown, and determining CM lethality. The critical role of brain endothelial cells (BECs) in fueling type I IFN\u2013driven brain inflammation was demonstrated in brain endothelial\u2013specific IFN\u03b2-reporter and STING1-deficient\n                    <jats:italic>Pba<\/jats:italic>\n                    -infected mice, which were significantly protected from CM lethality. Moreover, extracellular particles (EPs) released from\n                    <jats:italic>Pba<\/jats:italic>\n                    -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\/IFN\u03b2 in the brain endothelium, a process correlated with heme content. Notably, stimulation of STING1-deficient BECs with heme, docking experiments, and in\u00a0vitro 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\/IFN\u03b2\/CXCL10 axis crucial to CM pathogenesis and lethality.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2206327119","type":"journal-article","created":{"date-parts":[[2022,8,29]],"date-time":"2022-08-29T15:13:40Z","timestamp":1661786020000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":30,"title":["Brain endothelial STING1 activation by\n                    <i>Plasmodium<\/i>\n                    -sequestered heme promotes cerebral malaria via type I IFN response"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8855-4395","authenticated-orcid":false,"given":"Teresa F.","family":"Pais","sequence":"first","affiliation":[{"name":"Instituto Gulbenkian de Ci\u00eancia, 2780-156 Oeiras, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5817-7736","authenticated-orcid":false,"given":"Hajrabibi","family":"Ali","sequence":"additional","affiliation":[{"name":"Instituto Gulbenkian de Ci\u00eancia, 2780-156 Oeiras, Portugal"}]},{"given":"Joana","family":"Moreira da Silva","sequence":"additional","affiliation":[{"name":"Instituto Gulbenkian de Ci\u00eancia, 2780-156 Oeiras, Portugal"},{"name":"Centro de Investiga\u00e7\u00e3o Interdisciplinar em Sanidade Animal, Faculdade de Medicina Veterin\u00e1ria, Universidade de Lisboa, 1300-477 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4477-4492","authenticated-orcid":false,"given":"N\u00e1dia","family":"Duarte","sequence":"additional","affiliation":[{"name":"Instituto Gulbenkian de Ci\u00eancia, 2780-156 Oeiras, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1794-4377","authenticated-orcid":false,"given":"Rita","family":"Neres","sequence":"additional","affiliation":[{"name":"Instituto Gulbenkian de Ci\u00eancia, 2780-156 Oeiras, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5824-5209","authenticated-orcid":false,"given":"Chintan","family":"Chhatbar","sequence":"additional","affiliation":[{"name":"Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, Helmholtz Centre for Infection Research and the Hannover Medical School, 30625 Hannover, Germany"},{"name":"Institute of Neuropathology, Medical Faculty, University of Freiburg, D-79106 Freiburg, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3412-1903","authenticated-orcid":false,"given":"Rita C.","family":"Ac\u00farcio","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"}]},{"given":"Rita C.","family":"Guedes","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"}]},{"given":"Maria Carolina","family":"Strano Moraes","sequence":"additional","affiliation":[{"name":"Systems Oncology Group, Champalimaud Research, Champalimaud Centre for the Unknown, 1400-038 Lisbon, Portugal"}]},{"given":"Bruno","family":"Costa-Silva","sequence":"additional","affiliation":[{"name":"Systems Oncology Group, Champalimaud Research, Champalimaud Centre for the Unknown, 1400-038 Lisbon, Portugal"}]},{"given":"Ulrich","family":"Kalinke","sequence":"additional","affiliation":[{"name":"Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, Helmholtz Centre for Infection Research and the Hannover Medical School, 30625 Hannover, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7225-1907","authenticated-orcid":false,"given":"Carlos","family":"Penha-Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Instituto Gulbenkian de Ci\u00eancia, 2780-156 Oeiras, 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