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The biochemist and Nobel laureate Arthur Kornberg (1919-2007) titled his autobiography “For the Love of Enzymes”. Indeed, this was entirely appropriate because his life’s work was on the enzymes involved in the synthesis of DNA.

Erythrocytes infected with the human malaria parasite Plasmodium falciparum become structurally and antigenically modified as a consequence of intracellular parasite development. The new antigens that appear on the surface of the infected erythrocyte originate from parasite-encoded proteins and by modification of the erythrocyte membrane protein band 3. Here, we show that anti-peptide antibodies generated against an amino acid sequence (YETFSKLIKIFQDH) of human band 3, and previously identified as mediating adhesion of infected erythrocytes to CD36, recognized P. falciparum-infected erythrocytes. In addition, sera from individuals living in a malaria endemic area (and who are presumably immune) contained immunoglobulins specific for this region of band 3. The anti-peptide antibodies reacted with the surface excrescences (knobs) on falciparum-infected erythrocytes. In uninfected erythrocytes, the band 3 region was cryptic and its exposure on the falciparum-infected erythrocyte surface required clustering of band 3 protein. Thus, a parasite-induced modification of band 3 promotes adhesion and induces antigenic changes in the P. falciparum-infected erythrocyte.

Phosphatidylserine (PS) is a membrane phospholipid which in intact cells is exclusively localized in the inner leaflet of the lipid bilayer. However, once cells undergo apoptosis or oxidative stress, PS molecules are exposed on the external surface of the cells and this contributes to their adherence to macrophages or endothelial cells. PS exposure on Plasmodium falciparum-infected red cells was determined by flow cytometry using fluorescein-labeled annexin V, which specifically binds to PS. Involvement of exposed PS in the adherence of malaria-infected red cells to endothelial cells was examined by in vitro cytoadherence assays. Infected cells exposed PS on their surface as the intracellular parasites matured to trophozoite and schizont stages. Adherence of malaria-infected cells to CD36, CD36-expressing Chinese hamster ovary cells, thrombospondin, and C32 amelanotic melanoma cells was inhibited by annexin V, whereas ICAM-1- and chondroitin sulfate A-mediated binding was not. Further, PS liposomes and glycerophosphorylserine, but not phosphatidylcholine liposomes and glycerophosphorylcholine, inhibited the binding of infected cells to CD36 and thrombospondin. In conclusion, these results demonstrate that PS exposed on the surface of malaria-infected red cells contributes, in part, to the adherence of P. falciparum-parasitized red cells to CD36 and thrombospondin.

Historical records, some >3,000 years old, attest to the antiquity of the disease malaria. Using a light microscope, Alphonse Laveran noticed some crescent-shaped bodies among the red blood cells that were almost entirely transparent, save for some pigment inclusions. He recognized that these bodies were alive, and that he was looking at an animal parasite, not a bacterium or a fungus. Subsequently, he examined blood samples from 192 malaria patients: in 148 of these, he found the telltale crescents. Where there were no crescents, there were no symptoms of malaria. He named the parasite Oscillaria malariae and communicated his findings to the Societe Medicale des Hopitaux on 24 December 1880. Although malaria can be induced in a host by the introduction of parasites (called sporozoites) through the bite of an infectious female mosquito, the parasites do not immediately appear in the blood. This was surprising in view of the fact that in 1903 Fritz Schaudinn claimed to have seen sporozoites directly invade erythrocytes. All human malarial agents (Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae) are transmitted through the bite of an infected female anopheline mosquito when she injects sporozoites from her salivary glands during blood feeding. Investigations at the molecular level of enzyme structure, gene sequences, chromosomal arrangements, and transcriptional control will permit an uncovering of the adhesive molecules that mediate cell-cell interactions, determine the mechanisms of protein trafficking, and identify putative drug targets and vaccine candidates.