The role of complement in antibody-dependent acquired immunity to Plasmodium falciparum malaria

Many pathogens evade complement recognition by binding to complement regulatory proteins, such as factor H (FH), that protect host cells from complement attack. Asexual Plasmodium falciparum stages evade complement destruction by capturing FH on their surface. An initial study identified Pf92 as the only protein that interacts with FH; however, the Pf92 knockout transgenic parasites did not wholly abolish FH recruitment to the merozoite. Thus, I hypothesized that potentially, more merozoite proteins are involved in complement evasion. I used a combination of modified ELISA binding assay and surface plasmon resonance and tested a library of 110 recombinant merozoite proteins for interaction with FH. Protein microarray was used to measure antibody responses to the merozoite antigens that interacted with FH in a malaria longitudinal cohort of children. Additionally, I tested whether circulating levels of FH and the Y402H variant in the FH gene influence malaria severity. In addition to Pf92, I found seven additional merozoite proteins that interact with the FH, i.e. PF3D7_1105800, PF3D7_0206200, RH5, P12, PF3D7_1252300, PF3D7_0629500 (SEG) and P12p. Majority of the proteins bound to complement control protein modules (CCP) 5-7 of FH. Antibody responses against a combination of some of these merozoite FH receptor antigens were found to be associated with protective immunity. Children with severe malaria (SM) had markedly lower circulating FH levels compared to uncomplicated malaria (UM) controls (median: SM=269 ug/ml, UM=378 ug/ml, P=<0.0001). Besides, children homozygous for the Y402H variant had a slightly increased risk of severe malaria (OR 1.08 95% CI: 0.46-2.58 P=0.854) while those who were heterozygous had reduced risk (OR 0.62 95% CI: 0.30-1.28 P=0.195) when compared with normal individuals. These findings suggest that the Plasmodium falciparum parasite uses many proteins to interact with FH to avoid complement destruction and that FH protein, could be a vital host determinant for malaria severity. This study offers insights into the mechanisms of malaria parasite complement immune evasion and provides a rationale for future studies to evaluate stage-specific parasite proteins for interaction with complement regulatory proteins.