title: Transfer of 4-hydroxynonenal from parasitized to non-parasitized erythrocytes in rosettes. Proposed role in severe malaria anemia.
abstract: Severe anaemia is a life-threatening complication of falciparum malaria associated with loss of predominantly non-parasitized red blood cells (npRBCs). This poorly elucidated process might be influenced by (i) rosettes, i.e. npRBCs cytoadherent to haemozoin-containing parasitized RBCs (pRBCs) and (ii) generation in pRBCs of 4-hydroxynonenal (4-HNE) through haemozoin-catalysed lipid peroxidation. We explored whether close proximity in rosettes may facilitate 4-HNE transfer to npRBCs, which is likely to enhance their phagocytosis and contribute to malaria anaemia. Fluorescence microscopy and flow cytometry data indicated 4-HNE transfer to npRBCs in rosettes. Rosettes were formed by 64·8 ± 1·8% varO-expressing pRBCs, and 8·7 ± 1·1% npRBCs were positive for 4-HNE-protein-conjugates, while low-rosetting parasites generated only 2·4 ± 1·1% 4-HNE-conjugate-positive npRBCs. 4-HNE transfer decreased after blocking rosetting by monoclonal antibodies. A positive linear relationship between rosette frequency and 4-HNE-conjugates in npRBCs was found in 40 malaria patients, a first indication for a role of rosetting in npRBCs modifications in vivo. Children with severe malaria anaemia had significantly higher percentages of 4-HNE-conjugate-positive npRBCs compared to children with uncomplicated malaria. In conclusion, 4-HNE transfer from pRBCs to npRBCs in rosettes is suggested to play a role in the phagocytic removal of large numbers of npRBCs, the hallmark of severe malaria anaemia.
authors.affiliation: Department of Genetics, Biology and Biochemistry, University of Torino Medical School, Turin, Italy.
authors.forename: Sophie
authors.initials: S
authors.lastname: Uyoga
authors.forename: Oleksii A
authors.initials: OA
authors.lastname: Skorokhod
authors.forename: Michael
authors.initials: M
authors.lastname: Opiyo
authors.forename: Emily N
authors.initials: EN
authors.lastname: Orori
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Williams
authors.forename: Paolo
authors.initials: P
authors.lastname: Arese
authors.forename: Evelin
authors.initials: E
authors.lastname: Schwarzer
mesh_terms: D000447:Aldehydes / Q000378:metabolism*; D000740:Anemia / Q000097:blood* / Q000209:etiology / Q000469:parasitology*; D001692:Biological Transport; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology; D005260:Female; D006420:Hemeproteins / Q000378:metabolism; D006801:Humans; D007223:Infant; D015227:Lipid Peroxidation; D016778:Malaria, Falciparum / Q000097:blood* / Q000150:complications; D008297:Male; D010963:Plasmodium falciparum / Q000378:metabolism*
chemical_list: D000447:Aldehydes; D006420:Hemeproteins; C020753:hemozoin; C027576:4-hydroxy-2-nonenal