Anaemia is an important comorbidity of malaria, however, the mechanisms driving anaemia are unclear. Complement activation and loss of complement regulatory proteins (CRPs) on red blood cells (RBCs) has been identified to contribute to anaemia in Plasmodium falciparum infection, but its role in P. vivax is unknown. In contrast, antibodies that fix complement are major components in protective immunity against Plasmodium infection. We defined loss of CRPs in both P. falciparum and P. vivax anaemia, and determined if CRP loss was linked to complement-fixing antibodies.
RBCs from patients with P. falciparum (n=79) and P. vivax (n=42) malaria were collected from Papua, Indonesia, and from volunteers undergoing controlled human P. falciparum malaria infection (CHMI). Anaemia was categorised according to WHO criteria. Cytofluorometry was used to distinguish parasitised RBCs and to measure CRPs expression (CR1, CD55F, and CD59) on RBCs. Complement activation (C3a and C5a) and parasite-specific complement-fixing antibodies was measured by ELISA.
Expression of CR1 and CD55 were reduced in severe anaemia in both P. falciparum and P. vivax malaria. Reduction was restricted to uninfected RBCs, with infected RBC having higher levels of CRPs regardless of anaemia. CR1 and CD55 were also reduced in uninfected RBCs from volunteers during CHMI. There was no association between complement-fixing and CRPs RBC expression.
Our findings demonstrate the importance of reduced RBC CRPs expression in both P. falciparum and P. vivax malarial anaemia, and show that CRP loss is not linked to complement-fixing antibodies which have important role in malaria protection. Reduced CRPs was restricted to uninfected RBCs, likely contributing to the known vulnerability to destruction of the large uninfected RBC pool in malaria, and suggesting that parasites are relatively protected from complement-mediated destruction during infection. These findings provide clinically important insights into the pathogenesis of malaria anaemia.