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JCI Insight. 2018 Nov 15;3(22). pii: 124854. doi: 10.1172/jci.insight.124854. [Epub ahead of print]

Loss of complement regulatory proteins on uninfected erythrocytes in vivax and falciparum malaria anemia.

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Menzies School of Health Research and.
Charles Darwin University, Darwin, North Territory, Australia.
Mimika District Health Authority and.
Papuan Health and Community Development Foundation, Timika, Papua, Indonesia.
Department of Paediatrics, Faculty of Medicine, Gadjah Mada University, Yogyakarta, Central Java, Indonesia.
Burnet Institute, Melbourne, Victoria, Australia.
Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
Department of Microbiology and Central Clinical School, Monash University, Melbourne, Victoria, Australia.
Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.


Anemia is a major complication of malaria, driven largely by loss of uninfected RBCs during infection. RBC clearance through loss of complement regulatory proteins (CRPs) is a significant contributor to anemia in Plasmodium falciparum infection, but its role in Plasmodium vivax infection is unknown. CRP loss increases RBC susceptibility to macrophage clearance, a process that is also regulated by CD47. We compared CRPs and CD47 expression on infected and uninfected RBCs in adult patients with vivax and falciparum malaria and different anemia severities from Papua, Indonesia. Complement activation and parasite-specific complement-fixing antibodies were measured by ELISA. Levels of CR1 and CD55 were reduced in severe anemia in both falciparum and vivax malaria. Loss of CRPs and CD47 was restricted to uninfected RBCs, with infected RBCs having higher expression. There was no association among complement-fixing antibodies, complement activation, and CRP loss. Our findings demonstrate that CRP loss is a pan-species, age-independent mechanism of malarial anemia. Higher levels of CRP and CD47 expression on infected RBCs suggest that parasites are protected from complement-mediated destruction and macrophage clearance. Lack of associations between protective antibodies and CRP loss highlight that complement pathogenic and protective pathways are distinct mechanisms during infection.


Complement; Immunology; Infectious disease; Malaria

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