Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a family of proteins present on the membrane surface of red blood cells (RBCs or erythrocytes) that are infected by the malarial parasite Plasmodium falciparum. PfEMP1 is synthesized during the parasite's blood stage (erythrocytic schizogony) inside the RBC, during which the clinical symptoms of falciparum malaria are manifested. Acting as both an antigen and adhesion protein, it is thought to play a key role in the high level of virulence associated with P. falciparum. It was discovered in 1984 when it was reported that infected RBCs had unusually large-sized cell membrane proteins, and these proteins had antibody-binding (antigenic) properties. An elusive protein, its chemical structure and molecular properties were revealed only after a decade, in 1995. It is now established that there is not one but a large family of PfEMP1 proteins, genetically regulated (encoded) by a group of about 60 genes called var. Each P. falciparum is able to switch on and off specific var genes to produce a functionally different protein, thereby evading the host's immune system. RBCs carrying PfEMP1 on their surface stick to endothelial cells, which facilitates further binding with uninfected RBCs (through the processes of sequestration and rosetting), ultimately helping the parasite to both spread to other RBCs as well as bringing about the fatal symptoms of P. falciparum malaria.
Introduction
Malaria is the deadliest among infectious diseases, accounting for approximately 429,000 human deaths in 2015 as of the latest estimate by the World Health Organization. In humans, malaria can be caused by five Plasmodium parasites, namely P. falciparum, P. vivax, P. malariae, P. ovale and P. knowlesi. P. falciparum is the most dangerous species, attributed to >99% of malaria's death toll, with 70% of these deaths occurring in children under the age of five years. The parasites are transmitted through the bites of female mosquitos (of the species of Anopheles). Before invading the RBCs and causing the symptoms of malaria, the parasites first multiply in the liver. The daughter parasites called merozoites then only infect the RBCs. They undergo structural development inside the RBCs, becoming trophozoites and schizonts. It is during this period that malarial symptoms are produced.
Unlike RBCs infected by other Plasmodium species, P. falciparum-infected RBCs had been known to spontaneously stick together. By the early 1980s, it was established that when the parasite (both the trophozoite and schizont forms) enters the blood stream and infects RBCs, the infected cells form knobs on their surface. Then they become sticky, and get attached to the walls (endothelium) of the blood vessels through a process called cytoadhesion, or cytoadherence. Such attachment favours binding with and accumulation of other RBCs. This process is known as sequestration. It is during this condition that the parasites induce an immune response (antigen-antibody reaction) and evade destruction in the spleen. Although the process and significance of sequestration were described in detail by two Italian physicians Amico Bignami and Ettore Marchiafava in the early 1890s, it took a century to discover the actual factor for the stickiness and virulence.
Discovery
PfEMP1 was discovered by Russell J. Howard and his colleagues at the US National Institutes of Health in 1984. Using the techniques of radioiodination and immunoprecipitation, they found a unique but yet unknown antigen from P. falciparum-infected RBCs that appeared to cause binding with other cells. Since the antigenic protein could only be detected in infected cells, they asserted that the protein was produced by the malarial parasite, and not by RBCs. The antigen was large and appeared to be different in size in different strains of P. falciparum obtained from night monkey (Aotus). In one strain, called Camp (from Malaysia), the antigen was found to have a molecular size of approximately 285 kDa; while in the other, called St. Lucia (from El Salvador), it was approximately 260 kDa. Both antigens bind to cultured skin cancer (melanoma) cells. But the researchers failed to confirm whether or not the protein actually was an adhesion molecule to the wall of blood vessels. Later in the same year, they found out that the unknown antigen was associated only with RBCs having small lumps called knobs on their surface. The first human RBC antigen was reported in 1986. Howard's team found that the antigens from Gambian children, who were suffering from falciparum malaria, were similar to those from the RBCs of night monkey. They determined that the molecular sizes of the proteins ranged from 250 to 300 kDa.