Malaria is among the most serious infectious diseases affecting humans, accounting for approximately half a million deaths annually1. Plasmodium falciparum is the causative agent of most life-threatening malaria cases. Acquired immunity to malaria is inefficient, even after repeated exposures to P. falciparum2; 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 genome3, 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.
Human membrane cofactor protein (MCP, CD46) has been suggested, although no convincing evidence has been proposed, to be a fertilization-associated protein, in addition to its primary functions as a complement regulator and a measles virus receptor. We have cloned a cDNA encoding the murine homologue of MCP. This cDNA showed 45% identity in deduced protein sequence and 62% identity in nucleotide sequence with human MCP. Its ectodomains were four short consensus repeats and a serine/threonine-rich domain, and it appeared to be a type 1 membrane protein with a 23-amino acid transmembrane domain and a short cytoplasmic tail. The protein expressed on Chinese hamster ovary cell transfectants was 47 kDa on SDS/PAGE immunoblotting, approximately 6 kDa larger than the murine testis MCP. It served as a cofactor for factor I-mediated inactivation of the complement protein C3b in a homologous system and, to a lesser extent, in a human system. Strikingly, the major message of murine MCP was 1.5 kb and was expressed predominantly in the testis. It was not detected in mice defective in spermatogenesis or with immature germ cells (until 23 days old). Thus, murine MCP may be a sperm-dominant protein the message of which is expressed selectively in spermatids during germ-cell differentiation.
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