ArticleBlood advances2020
Parasite histones are toxic to brain endothelium and link blood barrier breakdown and thrombosis in cerebral malaria.
Article in Blood advances, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 51 citations in OpenAlex.
- The case for exploring innate memory in Plasmodium infection.Current opinion in microbiology · 2026Review
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- Mechanisms of parasite-mediated disruption of brain vessels.FEBS letters · 2026Review
- Plasmodium falciparum impairs Ang-1 secretion by pericytes in a 3D brain microvessel model.EMBO molecular medicine · 2025Article
- Plasmodium falciparum egress disrupts endothelial junctions and activates JAK-STAT signaling in a microvascular 3D blood-brain barrier model.Nature communications · 2025Article
- Nilotinib attenuates vascular pathology in experimental cerebral malaria.Blood advances · 2025Article
- In Silico Discovery of Antigenic-Secreted Proteins to Diagnostic Human Toxocariasis.Acta parasitologica · 2025Article
- Transcriptional responses of brain endothelium toMicrobiology spectrum · 2024Article
- A human pluripotent stem cell-derived in vitro model of the blood-brain barrier in cerebral malaria.Fluids and barriers of the CNS · 2024Article
- Unravelling mysteries at the perivascular space: a new rationale for cerebral malaria pathogenesis.Trends in parasitology · 2024Review
- Review
- Pathogenetic mechanisms and treatment targets in cerebral malaria.Nature reviews. Neurology · 2023Review
- Probing cerebral malaria inflammation in 3D human brain microvessels.Cell reports · 2023Article
- The role of the blood-brain barrier during neurological disease and infection.Biochemical Society transactions · 2023Review
- Fatal Case of a Child HarboringHealthcare (Basel, Switzerland) · 2023Article
- Elevated Levels of Procoagulant Microvesicles and Tissue-Factor Bearing Microvesicles in Malaria Patients.International journal of general medicine · 2023Article
- Different PfEMP1-expressing Plasmodium falciparum variants induce divergent endothelial transcriptional responses during co-culture.PloS one · 2023Article
- Dysregulated haemostasis in thrombo-inflammatory disease.Clinical science (London, England : 1979) · 2022Review
- The IL-33/ST2 Pathway in Cerebral Malaria.International journal of molecular sciences · 2022Review
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Authors and funding
20 authors at 9 institutions in 5 countries.
Funding
Abstract
Microvascular thrombosis and blood-brain barrier (BBB) breakdown are key components of cerebral malaria (CM) pathogenesis in African children and are implicated in fatal brain swelling. How Plasmodium falciparum infection causes this endothelial disruption and why this occurs, particularly in the brain, is not fully understood. In this study, we have demonstrated that circulating extracellular histones, equally of host and parasite origin, are significantly elevated in CM patients. Higher histone levels are associated with brain swelling on magnetic resonance imaging. On postmortem brain sections of CM patients, we found that histones are colocalized with P falciparum-infected erythrocytes sequestered inside small blood vessels, suggesting that histones might be expelled locally during parasite schizont rupture. Histone staining on the luminal vascular surface colocalized with thrombosis and leakage, indicating a possible link between endothelial surface accumulation of histones and coagulation activation and BBB breakdown. Supporting this, patient sera or purified P falciparum histones caused disruption of barrier function and were toxic to cultured human brain endothelial cells, which were abrogated with antihistone antibody and nonanticoagulant heparin. Overall, our data support a role for histones of parasite and host origin in thrombosis, BBB breakdown, and brain swelling in CM, processes implicated in the causal pathway to death. Neutralizing histones with agents such as nonanticoagulant heparin warrant exploration to prevent brain swelling in the development or progression of CM and thereby to improve outcomes.
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