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

Authors:
Open Access
Publisher website
Google Scholar
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.
Funding Information
  • National Institutes of Health (U19AI089676)
  • National Institutes of Health (U19AI181587)
  • Deutsches Zentrum für Infektionsforschung (TI 07.001_002)
  • Deutsches Zentrum für Infektionsforschung (TI 07.002)
  • Medical Research Council (UKRI1505)
  • Deutsche Forschungsgemeinschaft (SFB 1648/1 (2024) 512741711)
  • Else Kröner-Fresenius-Stiftung (2021_EKPK.10)
  • Werner Otto Stiftung (7/102)
  • Research Foundation Flanders (3G0A9322, 3G0AA824)
  • Foundation Against Cancer (365A08921, 365G09122)
  • EOS research consortium (3G0I5722)
  • UGent Special Research Fund Methusalem (01M00709)
  • University Medical Center Hamburg-Eppendorf

This publication has 89 references indexed in Scilit: