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CD8<sup>+</sup> T cells induce RIPK1-regulated brain endothelial cell death in cerebral malaria.

Overview

Authors: Alexandros Hadjilaou1,2,3, Phaidon Christodoulou1,2, Johannes Brandi2, Jan Broder Engler1, Ana Matcharashvili4,5, Tatiana Goncharov6, Carla Johnson7, Nikita Vladimirov8,9, Charlotte Schubert1, Sanjib Mohanty10,11, Praveen K. Sahu10,11, Linda Drewicke8, Sonja Binder12, Oliver Kretz4,5,13, Susanne Krasemann14, Lukas C. Bal1, Marcel S. Woo1, Sandra Konrath15, Dagmara McGuinness7, Vanessa Vieira1
and 19 other authorsUlricke Richardt2, Christiane Steeg2, Simone Bauer1, Terrie Taylor16, James Nyirenda7,16,17, Thomas Renné15, Karl B. Seydel16, Angelika Hoffmann18, Jens Kuhle19,20, Zhen Huang21, Peter Vandenabeele22,23, Andrew Woehler8, Christopher A. Moxon7,16, Markus Schwaninger12, Samuel C. Wassmer24, Victor G. Puelles4,5,25,26, Domagoj Vucic6, Thomas Jacobs2,3, Manuel A. Friese1
ORCID iDs: Alexandros Hadjilaou, Johannes Brandi, Jan Broder Engler, Ana Matcharashvili, Tatiana Goncharov, Carla Johnson, Nikita Vladimirov, Charlotte Schubert, Praveen K. Sahu, Linda Drewicke, Oliver Kretz, Susanne Krasemann, Lukas C. Bal, Marcel S. Woo, Sandra Konrath, Dagmara McGuinness, Vanessa Vieira, Christiane Steeg, Simone Bauer, Terrie Taylor, Thomas Renné, Karl B. Seydel, Jens Kuhle, Peter Vandenabeele, Andrew Woehler, Christopher A. Moxon, Markus Schwaninger, Victor G. Puelles, Domagoj Vucic, Thomas Jacobs, Manuel A. Friese
26 affiliations
  1. Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  2. Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine (BNITM), Hamburg, Germany
  3. German Center for Infection Research (DZIF), partner site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
  4. Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  5. III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  6. Department of Immunology Discovery, Genentech, San Francisco, CA, USA
  7. Center for Parasitology, School of Infection & Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
  8. Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, Berlin, Germany
  9. Brain Research Institute, University of Zurich, Zurich, Switzerland
  10. Department of Molecular Biology and Infectious Diseases, Community Welfare Society Hospital, Rourkela, Odisha, India
  11. Center for the Study of Complex Malaria in India, Ispat General Hospital, Rourkela, Odisha, India
  12. Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism, University of Lübeck, Lübeck, Germany
  13. Core Facility Electron Microscopy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  14. Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  15. Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  16. Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi
  17. Malawi-Liverpool-Wellcome Programme, Kamuzu University of Health Sciences, Blantyre, Malawi
  18. University Institute of Diagnostic and Interventional Neuroradiology, University Hospital Bern, Inselspital, University of Bern, Bern, Switzerland
  19. Department of Neurology, University Hospital Basel, Basel, Switzerland
  20. Departments of Biomedicine and Clinical Research, University of Basel, Basel, Switzerland
  21. Departments of Neuroscience and Neurology, University of Wisconsin-Madison, Madison, WI, USA
  22. VIB Center for Inflammation Research, VIB, Ghent B-9052, Belgium
  23. Department of Biomedical Molecular Biology, Ghent University, Ghent B-9052, Belgium
  24. Department of Infection Biology, London School of Hygiene and Tropical Medicine, London, UK
  25. Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
  26. Department of Pathology, Aarhus University Hospital, Aarhus, Denmark
Institutions: University Medical Center Hamburg-Eppendorf (Germany); German Center for Infection Research (Germany); Institute of Neuroimmunology and Multiple Sclerosis (Germany); Bernhard Nocht Institute for Tropical Medicine (Germany); Genentech (United States); University of Glasgow (United Kingdom); University of Zurich (Switzerland); Max Delbrück Center (Germany); Ispat General Hospital (India); Community Welfare Society Hospital (India); University of Lübeck (Germany); Kamuzu University of Health Sciences (Malawi); Malawi-Liverpool-Wellcome Trust Clinical Research Programme (Malawi); University of Bern (Switzerland); University Hospital of Bern (Switzerland); University of Basel (Switzerland); University Hospital of Basel (Switzerland); University of Wisconsin–Madison (United States); Ghent University (Belgium); VIB-UGent Center for Inflammation Research (Belgium); London School of Hygiene & Tropical Medicine (United Kingdom); Aarhus University (Denmark); Aarhus University Hospital (Denmark)
Journal: Science advances, volume 12, issue 45, article eaej4381
Dates: received 4 June 2026; accepted 5 October 2026; published online 6 November 2026; in print November 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1126/sciadv.aej4381 · PMID 42993832 · PMCID PMC13742144 · OpenAlex W7225414155
Open access: gold, a free copy (OpenAlex)
Status: dead link (how the code is found and verified)
Categories: human (organism), mouse (organism), cellular / molecular (subfield)
Methods: Statistics, Smoothing, state filtering, decompositions, Machine learning, Evoked potentials, Connectivity
MeSH: Brain*, CD8-Positive T-Lymphocytes*, Endothelial Cells*, Malaria, Cerebral*, Receptor-Interacting Protein Serine-Threonine Kinases*, Animals, Cell Death, Disease Models, Animal, Humans, Mice (* major topic)
Journal subjects: Immunology
Topic: Malaria Research and Control (Public Health, Environmental and Occupational Health, Medicine), according to OpenAlex
Funding: national institutes of health (U19AI089676, U19AI181587); Deutsches Zentrum für Infektionsforschung (TI 07.001_002, 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
Citations: not cited yet (Europe PMC); 91 references in the paper

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

No file of the authors' code could be read here: it is described below, and read at its source.

Zenodo 22685549

License: none: the authors keep all their rights
State: the link is dead, verified on 9 November 2026
Evidence: found in the paper
Software Heritage: not checked
Found in: “Data, code, and materials availability:”
Not found: README, license file, CITATION.cff, environment file, tests, continuous integration, documentation
Availability: 1 check, the latest on 9 November 2026: the link is dead (HTTP 404)
  • 9 November 2026: the link is dead (HTTP 404)
At the source: doi.org/10.5281/zenodo.22685549

The paper's code and data availability statement is in the Data section.

Tracing map

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Its JSON (tracing-map.json) is deposited on Zenodo with its DOI once the map is validated.

Data

Datasets cited

Data, code, and materials availability

All data and code needed to evaluate and reproduce the results in the paper are present in the paper and/or the Supplementary Materials. Raw RNA-seq data (TRAP-seq and CD8+ T cell transcriptomics) have been deposited in the Gene Expression Omnibus [dataset: TRAP-seq of brain endothelial cells, accession: GSE328812 (www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE328812); Dataset: RNA-seq of sorted CD8+ T cells, Accession: GSE328811 (www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE328811)]. Custom analysis scripts and Python notebooks, together with software dependencies and execution instructions, are publicly available at Zenodo (https://doi.org/10.5281/zenodo.22685549). MalariaGEN consortium GWAS summary statistics are publicly available at https://www.malariagen.net/. The GNE684 compound can be provided by D.V. pending scientific review and a completed material transfer agreement through Genentech. Requests for GNE684 should be submitted to: . The Mlklfl/fl mouse line can be provided by W. S. Alexander pending scientific review and a completed material transfer agreement through The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia. Requests for the Mlklfl/fl mouse line should be submitted to: . The Ripk1fl/fl and Ripk1D138N lines can be provided by M. Pasparakis pending scientific review and a completed material transfer agreement through the University of Cologne, Germany. Requests for the Ripk1fl/fl and Ripk1D138N lines should be submitted to: . The Slco1c1-CreERT2 mouse line can be provided by M.S. pending scientific review and a completed material transfer agreement through the University of Lübeck, Germany. Requests for the Slco1c1-CreERT2 mouse line should be submitted to: . The Casp3fl/fl and Casp7fl/fl mouse lines can be provided by P.V. pending scientific review and a completed material transfer agreement through University of Ghent, Belgium. Requests for the Casp3fl/fl and Casp7fl/fl mouse lines should be submitted to: . All other materials and reagents are commercially available as described in the Materials and Methods and table S5.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 9 November 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 39 authors, 10 MeSH terms, 11 funders, 89 references.

Cite

This paper

Hadjilaou, A., Christodoulou, P., Brandi, J., Engler, J. B., Matcharashvili, A., Goncharov, T., Johnson, C., Vladimirov, N., Schubert, C., Mohanty, S., Sahu, P. K., Drewicke, L., Binder, S., Kretz, O., Krasemann, S., Bal, L. C., Woo, M. S., Konrath, S., McGuinness, D., . . . Friese, M. A. (2026). CD8<sup>+</sup> T cells induce RIPK1-regulated brain endothelial cell death in cerebral malaria. Science advances, 12(45), eaej4381. https://doi.org/10.1126/sciadv.aej4381

BibTeX

@article{hadjilaou2026cd8,
author = {Hadjilaou, Alexandros and Christodoulou, Phaidon and Brandi, Johannes and Engler, Jan Broder and Matcharashvili, Ana and Goncharov, Tatiana and Johnson, Carla and Vladimirov, Nikita and Schubert, Charlotte and Mohanty, Sanjib and Sahu, Praveen K. and Drewicke, Linda and Binder, Sonja and Kretz, Oliver and Krasemann, Susanne and Bal, Lukas C. and Woo, Marcel S. and Konrath, Sandra and McGuinness, Dagmara and Vieira, Vanessa and Richardt, Ulricke and Steeg, Christiane and Bauer, Simone and Taylor, Terrie and Nyirenda, James and Renné, Thomas and Seydel, Karl B. and Hoffmann, Angelika and Kuhle, Jens and Huang, Zhen and Vandenabeele, Peter and Woehler, Andrew and Moxon, Christopher A. and Schwaninger, Markus and Wassmer, Samuel C. and Puelles, Victor G. and Vucic, Domagoj and Jacobs, Thomas and Friese, Manuel A.},
title = {{CD8\<sup\>+\</sup\> T cells induce RIPK1-regulated brain endothelial cell death in cerebral malaria}},
journal = {Science advances},
year = {2026},
month = nov,
volume = {12},
number = {45},
pages = {eaej4381},
publisher = {American Association for the Advancement of Science},
issn = {2375-2548},
doi = {10.1126/sciadv.aej4381},
url = {https://doi.org/10.1126/sciadv.aej4381},
pmid = {42993832},
pmcid = {PMC13742144}
}

RIS

TY - JOUR
AU - Hadjilaou, Alexandros
AU - Christodoulou, Phaidon
AU - Brandi, Johannes
AU - Engler, Jan Broder
AU - Matcharashvili, Ana
AU - Goncharov, Tatiana
AU - Johnson, Carla
AU - Vladimirov, Nikita
AU - Schubert, Charlotte
AU - Mohanty, Sanjib
AU - Sahu, Praveen K.
AU - Drewicke, Linda
AU - Binder, Sonja
AU - Kretz, Oliver
AU - Krasemann, Susanne
AU - Bal, Lukas C.
AU - Woo, Marcel S.
AU - Konrath, Sandra
AU - McGuinness, Dagmara
AU - Vieira, Vanessa
AU - Richardt, Ulricke
AU - Steeg, Christiane
AU - Bauer, Simone
AU - Taylor, Terrie
AU - Nyirenda, James
AU - Renné, Thomas
AU - Seydel, Karl B.
AU - Hoffmann, Angelika
AU - Kuhle, Jens
AU - Huang, Zhen
AU - Vandenabeele, Peter
AU - Woehler, Andrew
AU - Moxon, Christopher A.
AU - Schwaninger, Markus
AU - Wassmer, Samuel C.
AU - Puelles, Victor G.
AU - Vucic, Domagoj
AU - Jacobs, Thomas
AU - Friese, Manuel A.
TI - CD8<sup>+</sup> T cells induce RIPK1-regulated brain endothelial cell death in cerebral malaria
T2 - Science advances
J2 - Sci Adv
PY - 2026
DA - 2026/11/06
VL - 12
IS - 45
SP - eaej4381
SN - 2375-2548
PB - American Association for the Advancement of Science
DO - 10.1126/sciadv.aej4381
UR - https://doi.org/10.1126/sciadv.aej4381
LA - en
ER -

CSL-JSON

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