CD8 + T cells induce RIPK1-regulated brain endothelial cell death in cerebral malaria

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.

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Publication Details

Journal
Science Advances
Published
2026-11-06
DOI
https://doi.org/10.1126/sciadv.aej4381
Primary Topic
Malaria Research and Control
Type
article
Field-Weighted Citation Impact
0.00

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article

CD8 + T cells induce RIPK1-regulated brain endothelial cell death in cerebral malaria

Andrew Woehler, Christopher A. Moxon, Sanjib Mohanty, Markus Schwaninger et al.
1 links
Science Advances
Malaria Research and Control
article

CD8 + T cells induce RIPK1-regulated brain endothelial cell death in cerebral malaria

Andrew Woehler, Christopher A. Moxon, Sanjib Mohanty, Markus Schwaninger, Samuel Crocodile Wassmer, Jan Broder Engler, Manuel Alexander Friese, Praveen Kishore Sahu, Christiane Steeg, Lukas Can Bal, Simone Bauer, Susanne Krasemann, Vanessa Vieira, Terrie Ellen Taylor, Marcel S. Woo, Johannes Brandi, Alexandros Hadjilaou, Thomas Renné, Sonja Binder, Victor G. Puelles, Jens Kühle, Sandra Konrath, Domagoj Vucic, Tatiana Goncharov, Ulricke Richardt, Karl B. Seydel, Dagmara McGuinness, Angelika Hoffmann, Nikita Vladimirov, Oliver Kretz, Peter Vandenabeele, Zhen Huang, Thomas Jacobs, Charlotte Schubert, Carla Johnson, James Nyirenda, Linda Drewicke, Phaidon Christodoulou, Ana Matcharashvili
article en

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.

Science AdvancesVol. 12(45)
University of Bern (CH), University of Wisconsin–Madison (US), Genentech (US), University of Basel (CH), University of Zurich (CH), Aarhus University (DK), Max Delbrück Center (DE), Malawi-Liverpool-Wellcome Trust Clinical Research Programme (MW), University Hospital of Bern (CH), Aarhus University Hospital (DK), University Hospital of Basel (CH), Ghent University (BE), London School of Hygiene & Tropical Medicine (GB), Ispat General Hospital (IN), University Medical Center Hamburg-Eppendorf (DE), German Center for Infection Research (DE), VIB-UGent Center for Inflammation Research (BE), Community Welfare Society Hospital (IN), Kamuzu University of Health Sciences (MW), Institute of Neuroimmunology and Multiple Sclerosis (DE), University of Glasgow (GB), University of Lübeck (DE), Bernhard Nocht Institute for Tropical Medicine (DE)
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
Good health and well-being
Openalex Percentile: Top 12%
Malaria Research and Control
DOIOpen Access PDFOpenAlex
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