Abstract
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.
Highlights
Malaria continues to cause major morbidity and mortality globally; it is responsible for approximately 216 million clinical cases and 445,000 deaths annually [1]
Expression of complement regulatory proteins (CRPs) on uninfected and infected RBCs, plasma complement activation, and complement-fixing antibodies were assessed in 121 patients, 79 with P. falciparum and 42 with P. vivax malaria
CR1 and CD55 on uninfected RBCs are reduced in P. falciparum malaria with severe anemia
Summary
Malaria continues to cause major morbidity and mortality globally; it is responsible for approximately 216 million clinical cases and 445,000 deaths annually [1]. Clinical malaria cases are predominantly caused by Plasmodium falciparum and Plasmodium vivax infection. Anemia is a common clinical manifestation of malaria and a major cause of morbidity and mortality among young children and pregnant women [2, 3]. The pathogenic mechanisms of malarial anemia are complex, multifactorial, and not fully defined, for vivax malaria [4, 5]. Malarial anemia is not due to parasite destruction of infected RBCs but rather results predominately from the loss of uninfected RBCs. For each loss of 1 infected RBC, it is estimated that an additional 8 uninfected RBCs are removed in P. falciparum [2, 6] and 34 in P. vivax infection [7]. The mechanisms underlying this specific loss of uninfected RBCs are poorly understood
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