Plasmodium falciparum erythrocyte membrane protein 1
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 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.
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.
Then they become sticky, and get attached to the walls (endothelium) of the blood vessels through a process called cytoadhesion, or cytoadherence.
[6] It is during this condition that the parasites induce an immune response (antigen-antibody reaction) and evade destruction in the spleen.
[7][8] 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.
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.
But the researchers failed to confirm whether or not the protein actually was an adhesion molecule to the wall of blood vessels.
[12] 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.
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.
[16] Although some of the properties of PfEMP1 were firmly established, the protein was difficult to isolate due to its low occurrence.
Five years after its discovery, one of the original researchers Irwin Sherman began to doubt the existence of PfEMP1 as a unique protein.
[19] Xin-Zhuan Su and others showed that there could be more than 50 var genes which are distributed on different chromosomes of the malarial parasite.
[21] The wide range of molecular size reflects extreme variation in the amino acid composition of the proteins.
It consists of a number of sub-domains, including a short and conserved N terminal segment (NTS) at the outermost region, followed by a highly variable Duffy-binding-like (DBL) domain, sometimes a Ca2+-binding C2 domain, and then one or two cysteine-rich interdomain regions (CIDRs).
[23] There are six variant types of DBL, named DBLα, DBLβ, DBLγ, DBLδ, DBLε and DBLζ.
The TMD and ATS are highly conserved among different PfEMP1s,[27] and their structures have been solved using solution NMR (PDB: 2LKL).
The DBL-CIDR combination in a particular type of PfEMP1 protein is never random, but organized into specific sequences known as domain cassettes.
[26] Within the cytoplasm, the newly synthesized protein is attached to a Golgi-like membranous vesicle called the Maurer's cleft.
[48] These knobs are easily identified as conspicuous bumps on the infected RBCs from the early trophozoite stage onward.
[52] To form a knob, KAHRP aggregates several membrane skeletal proteins of the host RBC, such as spectrin, actin, ankyrin R, and spectrin–actin band 4.1 complex.
The most important binding properties of P. falciparum known to date are mediated by the head structure of PfEMP1, consisting of DBL domains and CIDRs.
[61] The DBLα-CIDRγ tandem pair is the main factor for rosetting,[64] sticking together the infected RBC with the uninfected cells, and thereby clogging of the blood vessels.
In P. falciparum-prevalent regions in Africa, pregnant women are found to contain high levels of antibody (immunoglobulin G, or IgG) against VAR2CSA, which protect them the placenta-attacking malarial parasite.
[33] In a normal human immune system, malarial parasite binding to RBCs stimulates the production of antibodies that attack the PfEMP1 molecules.
Binding of VAR2CSA to CSA is the primary cause of premature delivery, death of the foetus and severe anaemia in the mother.
[72] This indicates that drugs targeting VAR2CSA will be able to prevent the effects of malaria, and for this reason VAR2CSA is the leading candidate for development of a PAM vaccine.
