title: Digestive vacuole of Plasmodium falciparum released during erythrocyte rupture dually activates complement and coagulation.
abstract: Severe Plasmodium falciparum malaria evolves through the interplay among capillary sequestration of parasitized erythrocytes, deregulated inflammatory responses, and hemostasis dysfunction. After rupture, each parasitized erythrocyte releases not only infective merozoites, but also the digestive vacuole (DV), a membrane-bounded organelle containing the malaria pigment hemozoin. In the present study, we report that the intact organelle, but not isolated hemozoin, dually activates the alternative complement and the intrinsic clotting pathway. Procoagulant activity is destroyed by phospholipase C treatment, indicating a critical role of phospholipid head groups exposed at the DV surface. Intravenous injection of DVs caused alternative pathway complement consumption and provoked apathy and reduced nociceptive responses in rats. Ultrasonication destroyed complement-activating and procoagulant properties in vitro and rendered the DVs biologically inactive in vivo. Low-molecular-weight dextran sulfate blocked activation of both complement and coagulation and protected animals from the harmful effects of DV infusion. We surmise that in chronic malaria, complement activation by and opsonization of the DV may serve a useful function in directing hemozoin to phagocytic cells for safe disposal. However, when the waste disposal system of the host is overburdened, DVs may transform into a trigger of pathology and therefore represent a potential therapeutic target in severe malaria.
authors.affiliation: Department of Medical Microbiology and Hygiene, University Medical Center, Johannes Gutenberg University, Hochhaus Augustusplatz, Mainz, Germany.
authors.forename: Prasad
authors.initials: P
authors.lastname: Dasari
authors.forename: Sophia D
authors.initials: SD
authors.lastname: Heber
authors.forename: Maike
authors.initials: M
authors.lastname: Beisele
authors.forename: Michael
authors.initials: M
authors.lastname: Torzewski
authors.forename: Kurt
authors.initials: K
authors.lastname: Reifenberg
authors.forename: Carolin
authors.initials: C
authors.lastname: Orning
authors.forename: Anja
authors.initials: A
authors.lastname: Fries
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Zapf
authors.forename: Stefan
authors.initials: S
authors.lastname: Baumeister
authors.forename: Klaus
authors.initials: K
authors.lastname: Lingelbach
authors.forename: Rachanee
authors.initials: R
authors.lastname: Udomsangpetch
authors.forename: Sebastian Chakrit
authors.initials: SC
authors.lastname: Bhakdi
authors.forename: Karina
authors.initials: K
authors.lastname: Reiss
authors.forename: Sucharit
authors.initials: S
authors.lastname: Bhakdi
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects / Q000502:physiology*; D003170:Complement Pathway, Alternative / Q000187:drug effects / Q000502:physiology*; D016264:Dextran Sulfate / Q000494:pharmacology; D004912:Erythrocytes / Q000469:parasitology*; D006420:Hemeproteins / Q000502:physiology; D006461:Hemolysis; D006801:Humans; D006987:Hypesthesia / Q000209:etiology; D007425:Intracellular Membranes / Q000502:physiology; D008168:Lung / Q000469:parasitology; D016778:Malaria, Falciparum / Q000097:blood / Q000150:complications / Q000276:immunology / Q000469:parasitology; D008297:Male; D009000:Monocytes / Q000469:parasitology; D017288:Pain Threshold; D010587:Phagocytosis; D010963:Plasmodium falciparum / Q000254:growth & development / Q000502:physiology* / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000469:parasitology; D014617:Vacuoles / Q000502:physiology*
chemical_list: D006420:Hemeproteins; C020753:hemozoin; D016264:Dextran Sulfate