**12. Erythrocyte and other organisms, particularly plasmodium**

Erythrocytes interact with several organisms like bacteria and Plasmodium. Erythrocytes also interact with viruses, although mainly through adherence of viruses to erythrocyte membrane proteins or glycocalyx. Several erythrocyte membrane proteins are known as receptors for Plasmodium, somewhat dependent on the Plasmodium species. An interesting aspect is that Plasmodium seems to be dependent on iron acquired directly from hemoglobin of the erythrocyte. For instance, Plasmodium cannot obtain iron from heme. The erythrocyte is made dependent on the Plasmodium parasite by the glutathione synthesis of the parasite, whereas the erythrocytes own glutathione synthesis seems to be largely turned off [170]. Glutathione export from the Plasmodium-infected erythrocyte proceeds mainly in the oxidized (GSSG) form probably reflecting conditions of oxidative stress under infection. Erythrocytes infected with Plasmodium produce microvesicles that contain miR451, let7, and Argonaute2 protein together forming a functional RISC complex [167]. Plasmodium does not contain the genes necessary for miRNA production, but human miRNA and Argonaute protein have been detected in Plasmodium, presumably transferred from the erythrocyte by microvesicles. Infected erythrocytes also produce microvesicles that can be transferred to endothelial cells, astrocytes, and microglia [171]. Plasmodium causes profound changes in the erythrocyte plasma membrane, which can become almost devoid of cholesterol and display phosphatidylserine [172]. Absence of cholesterol makes the plasma membrane susceptible to pore formation by granulysin, a pore-forming peptide produced by cytotoxic cells like gamma-delta T cells. Exoplasmic phosphatidylserine may make the cells less susceptible to perforin, another pore-forming peptide. Infected erythrocytes display PfEMP (Plasmodium falciparum erythrocyte membrane protein) which binds to receptors on endothelial cells and thereby prevents circulation of infected erythrocytes. Although they may display phosphatidylserine, infected erythrocytes are consequently not easily cleared from circulation by spleen macrophages. PfEMP can be recognized by gamma-delta T cells of the host, but the parasite can change the expressed PfEMP, since it contains about 60 different PfEMPs. Although malaria is usually not fatal, cerebral malaria caused by Plasmodium falciparum can be fatal particularly in children. Cerebral malaria involves a partial disruption of the blood-brain barrier [173]. This probably comes about through phagocytosis of infected erythrocytes by endothelial cells in brain capillaries, followed by presentation of Plasmodium antigens on the endothelial cell and attack from alfa-beta Tcells [173].
