P. falciparum HRP2 Protein

Malaria is the most widespread infectious disease in the tropics and subtropics, with high levels of morbidity and mortality. An estimated 3.3 billion people worldwide are at risk of malaria, of whom 1.2 billion are at high risk, and sustained malaria transmission exists in 97 countries. Plasmodium falciparum is a major cause of mass mortality compared to other malaria parasites. Plasmodium falciparum is present in both female Anopheles vectors and human hosts. In Anopheles, the life cycle of Plasmodium falciparum begins when the mosquito ingests gametocytes. In the mosquito's intestine gametocytes differentiate into gametes and are fertilized to form zygotes. Zygotes differentiate into ookinetes and develop into oocysts. out of a thousand gametocytes, only 50-100 differentiate into ookinetes and only about 5 develop into oocysts. Subsequently, ookinetes invade the midgut epithelium using mosquito sugars and parasite lectins, on the other hand oocysts develop and produce thousands of sporozoites that invade the salivary glands. Infected mosquitoes release sporozoites in the human body during blood-sucking. Sporozoites invade hepatocytes via the cholesterol uptake pathway, and in stem cells it is encapsulated in parasitic vesicles to avoid lysosomal degradation. Within 60 seconds after sporozoites invade the hepatocyte, 10,000 to 30,000 merozoites leave the sporozoites.

Figure 1. Life cycle of Plasmodium falciparum
(Source: Nilsson SK, et al. 2015)

The first Plasmodium histidine-rich protein (HRP) was discovered in the last century while studying the avian parasite Plasmodium lophurae, which has characteristic cytoplasmic granules, and from these granules the researchers extracted a protein from which histidine residues accounted for more than 70%. In Plasmodium falciparum, the genes encoding HRP are all located in highly variable subtelomeric chromosomal regions, coexisting with antigenic variant polygenic families. Each gene contains two exons and two introns, with the first exon and the start of the second exon encoding signaling and cleavage sequences. The major histidine-rich sequences of pfhrp2 and pfhrp3 are located within the second exon, are of low complexity, and encode mainly tripeptide or hexapeptide repeats.

The exact functional role of HRP2 remains unclear and is currently thought to be involved in the detoxification of iron-containing heme groups produced by digestion of host hemoglobin. In vitro, HRP2 binds to a large number of heme molecules and can catalyze the formation of haemozoin from heme crystals through a scaffold-like function, as well as neutralize haem in the erythrocyte cytoplasm and remove it from the erythrocyte membrane. A key event in the characterization of Plasmodium falciparum malaria and in the pathogenesis of severe malaria is the isolation of infected erythrocytes in postcapillary venules, a process that allows the parasite to bypass splenic filtration of the mature parasite stages. HRP2 may be involved in erythrocyte cytoskeletal changes and may also disrupt the integrity of the blood-brain barrier by activating inflammasomes, leading to increased expression of cell adhesion molecules on the endothelial surface, which promotes cell adhesion and thus avoids removal by the spleen.

Plasmodium falciparum HRP2 Protein