Immune evasion of Plasmodium falciparum by RIFIN via inhibitory receptors

Malaria is among the most serious infectious diseases affecting humans, accounting for approximately half a million deaths annually(1). Plasmodium falciparum is the causative agent of most life-threatening malaria cases. Acquired immunity to malaria is inefficient, even after repeated exposures to P. falciparum(2); immune regulatory mechanisms employed by P. falciparum remain largely unclear. Here, we show that P. falciparum uses immune inhibitory receptors for immune evasion. RIFINs, products of a polymorphic multigene family comprising approximately 150–200 genes per parasite genome(3), are expressed on the surface of infected erythrocytes. We found that a subset of RIFINs binds to either leucocyte immunoglobulin-like receptor B1 (LILRB1) or leucocyte-associated immunoglobulin-like receptor 1 (LAIR1). LILRB1-binding RIFINs inhibited activation of LILRB1-expressing B cells and NK cells. Furthermore, interactions between LILRB1 and P. falciparum-infected erythrocytes isolated from malaria patients were associated with severe malaria, although an extended study with larger sample sizes is required to confirm the findings. These results suggest that P. falciparum has acquired multiple RIFINs to evade the host immune system by targeting immune inhibitory receptors.