Transfer of 4‐hydroxynonenal from parasitized to non‐parasitized erythrocytes in rosettes. Proposed role in severe malaria anemia

SummarySevere 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.