title: Malarial anemia: digestive vacuole of Plasmodium falciparum mediates complement deposition on bystander cells to provoke hemophagocytosis.
abstract: The digestive vacuole (DV) of Plasmodium falciparum, which is released into the bloodstream upon rupture of each parasitized red blood cell (RBC), was recently discovered to activate the alternative complement pathway. In the present work, we show that C3- and C5-convertases assembling on the parasitic organelle are able to provoke deposition of activated C3 and C5b-9 on non-infected bystander erythrocytes. Direct contact of DVs with cells is mandatory for the effect, and bystander complement deposition occurs focally, possibly at the sites of contact. Complement opsonization promotes protracted erythrophagocytosis by human macrophages, an effect that is magnified when ring-stage infected RBCs with reduced CD55 and CD59, or paroxysmal nocturnal hemoglobinuria (PNH)-RBCs lacking these complement inhibitors are employed as targets. Bystander attack can also directly induce lysis of PNH-RBCs. Direct evidence for complement activation and bystander attack mediated by DVs was obtained through immunohistochemical analyses of brain paraffin sections from autopsies of patients who had died of cerebral malaria. C3d and the assembled C5b-9 complex could be detected in all sections, colocalizing with and often extending locally beyond massive accumulations of DVs that were identified under polarized light. This is the first demonstration that a complement-activating particle can mediate opsonization of bystander cells to promote their antibody-independent phagocytosis. The phenomenon may act in concert with other pathomechanisms to promote the development of anemia in patients with severe malaria.
authors.affiliation: Department of Medical Microbiology and Hygiene, University Medical Center, Johannes Gutenberg University Mainz, Hochhaus Augustusplatz, 55202, Mainz, Germany.
authors.forename: Prasad
authors.initials: P
authors.lastname: Dasari
authors.forename: Anja
authors.initials: A
authors.lastname: Fries
authors.forename: Sophia D
authors.initials: SD
authors.lastname: Heber
authors.forename: Abdulgabar
authors.initials: A
authors.lastname: Salama
authors.forename: Igor-Wolfgang
authors.initials: IW
authors.lastname: Blau
authors.forename: Klaus
authors.initials: K
authors.lastname: Lingelbach
authors.forename: Sebastian Chakrit
authors.initials: SC
authors.lastname: Bhakdi
authors.forename: Rachanee
authors.initials: R
authors.lastname: Udomsangpetch
authors.forename: Michael
authors.initials: M
authors.lastname: Torzewski
authors.forename: Karina
authors.initials: K
authors.lastname: Reiss
authors.forename: Sucharit
authors.initials: S
authors.lastname: Bhakdi
mesh_terms: D001921:Brain / Q000473:pathology; D024201:Bystander Effect; D003165:Complement System Proteins / Q000276:immunology* / Q000378:metabolism*; D004912:Erythrocytes / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D010587:Phagocytosis; D010963:Plasmodium falciparum / Q000276:immunology*; D014617:Vacuoles / Q000276:immunology*
chemical_list: D003165:Complement System Proteins