Antibody-independent activation of complement and its regulation on multiple membrane layers of Plasmodium falciparum-infected erythrocytes

Malaria, caused by Plasmodium falciparum, remains a significant health burden, especially in tropical regions, as the parasite develops within human red blood cells (RBCs). The complement system initiates an early immune response against the parasite, but P. falciparum effectively evades complement-mediated killing. This study investigates how complement proteins deposit and are regulated on infected RBCs (iRBCs) and merozoites in the absence of parasite-specific antibodies. We show that factor H, a key complement regulator, binds directly to parasite plasma membranes (PPM), and CD59—a host glycosylphosphatidylinositol-anchored membrane attack complex (MAC) inhibitor—is transferred to the parasitophorous vacuole membrane (PVM) surrounding the parasite within RBCs. These processes limit the formation of the MAC and prevent complement-mediated lysis of the iRBCs. The study reveals structure-specific complement deposition, with C1q binding to the PPM, while C5b-9 assembles on the PVM, although C9 remains partially polymerized. These findings challenge previous assumptions by demonstrating that complement regulators act at multiple structural levels to support parasite survival. This nuanced strategy balances complement activation and regulation, helping P. falciparum evade immune attack while preserving RBC integrity. Understanding these mechanisms opens new avenues for complement-targeted therapies aimed at enhancing immune clearance or disrupting parasite development during blood-stage infection.