CD8 + T cells induce RIPK1-regulated brain endothelial cell death in cerebral malaria
Year: 2026
Type: article
Abstract: Cerebral malaria (CM) is a potentially lethal complication of Plasmodium falciparum infection characterized by blood-brain barrier disruption and brain hemorrhage. Although immune-mediated endothelial damage is central to CM pathology, the mechanisms linking cytotoxic immune responses to endothelial injury remain unclear. Here, we show that CD8 + T cells induce receptor-interacting serine/threonine-protein kinase 1 (RIPK1)–regulated cell death of brain endothelial cells in mouse CM, while RIPK1 phosphorylation is increased in brain endothelial cells in human CM. Using magnetic resonance imaging, three-dimensional tissue-cleared brain imaging, cross-species pathology, endothelial translatomics, immunocerebrovascular interactomics, and genetic association testing, we identify a CD8 + T cell–dependent, RIPK1-centered mouse endothelial cell death program. Combined RIPK1 and caspase inhibition protected cross-presenting endothelial cells from CD8 + T cell–mediated death in vitro. In vivo, brain endothelial-specific genetic inactivation or systemic pharmacological inhibition of RIPK1 kinase activity prolonged survival in mouse CM without altering parasitemia. These findings support RIPK1 inhibition as a promising therapeutic strategy to counter CD8 + T cell–induced endothelial death in CM.
Source: Science Advances
Authors: Alexandros Hadjilaou, Phaidon Christodoulou, Johannes Brandi, Jan Broder Engler, Ana Matcharashvili, Tatiana Goncharov, Carla Johnson, Nikita Vladimirov, Charlotte Schubert, Sanjib Mohanty, Praveen K. Sahu, Linda Drewicke, Sonja Binder, Oliver Kretz, Susanne Krasemann, Lukas C. Bal, Marcel S. Woo, Sandra Konrath, Dagmara McGuinness, Vanessa Vieira, Ulricke Richardt, Christiane Steeg, Simone Bauer, Terrie Taylor, James Nyirenda, Thomas Renné, Karl B. Seydel, Angelika Hoffmann, Jens Kuhle, Zhen Huang, Peter Vandenabeele, Andrew Woehler, Christopher A. Moxon, Markus Schwaninger, Samuel C. Wassmer, Victor G. Puelles, Domagoj Vucic, Thomas Jacobs, Manuel A. Friese
Institutions: University Medical Center Hamburg-Eppendorf, German Center for Infection Research, Institute of Neuroimmunology and Multiple Sclerosis, Bernhard Nocht Institute for Tropical Medicine, Genentech, University of Glasgow, University of Zurich, Max Delbrück Center, Ispat General Hospital, Community Welfare Society Hospital, University of Lübeck, Kamuzu University of Health Sciences, Malawi-Liverpool-Wellcome Trust Clinical Research Programme, University of Bern, University Hospital of Bern, University of Basel, University Hospital of Basel, University of Wisconsin–Madison, Ghent University, VIB-UGent Center for Inflammation Research, London School of Hygiene & Tropical Medicine, Aarhus University, Aarhus University Hospital
Language: English
Topic: Malaria Research and Control
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,500
Funders: Deutsches Zentrum für Infektionsforschung, Deutsche Forschungsgemeinschaft, Else Kröner-Fresenius-Stiftung, Fonds Wetenschappelijk Onderzoek, Fondation contre le Cancer, Werner Otto Stiftung, National Institutes of Health, Medical Research Council, Universitätsklinikum Hamburg-Eppendorf, National Institute of Allergy and Infectious Diseases
OpenAlex ID: W7225414155