Parasite histones mediate leak and coagulopathy in cerebral malaria
| Autor: | Cheng Hock Toh, Michael J. Potchen, Malcolm E. Molyneux, George F. Murphy, James S. O’Donnell, Terrie E. Taylor, Niamh O’Regan, Simon T. Abrams, Joo Yeon Ko, Julien M.H. Toh, Karl B. Seydel, Guillermo García-Cardeña, Alister Craig, Christopher A. Moxon, Yasir Alhamdi, Sam Kampondeni, Guozheng Wang, Janet Storm |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
Endothelium biology business.industry Plasmodium falciparum Heparin Human brain 030204 cardiovascular system & hematology Pharmacology biology.organism_classification Blood–brain barrier 3. Good health Endothelial activation 03 medical and health sciences 0302 clinical medicine medicine.anatomical_structure Histone Cerebral Malaria parasitic diseases medicine biology.protein business 030304 developmental biology medicine.drug |
| DOI: | 10.1101/563551 |
| Popis: | Coagulopathy and leak, specific to the brain vasculature, are central pathogenetic components of cerebral malaria (CM). It is unclear how the parasite, Plasmodium falciparum, triggers these processes. Extracellular histones, released from damaged host cells, bind to cell membranes and cause coagulation activation, platelet aggregation and vascular leak in diverse critical illnesses. In CM patients with P. falciparum, serum histones correlate with fibrin formation, thrombocytopenia, and endothelial activation and predict brain swelling on magnetic resonance imaging and fatal outcome. Post-mortem, histones bind to the luminal vascular surface, co-localizing with P. falciparum-infected erythrocytes (IE), and with thrombosis and leak. Purified P. falciparum histones cause toxicity and barrier disruption in cultured human brain microvascular endothelial cells, as does serum from CM patients, reversed by anti-histone antibodies and non-anticoagulant heparin. These data implicate parasite histones as a key trigger of fatal brain swelling in CM. Neutralizing histones with agents such as non-anticoagulant heparin warrant exploration to prevent brain swelling and improve outcome. |
| Databáze: | OpenAIRE |
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