Malaria-infected red cell

Most of the work on membrane transport with malaria parasites prior to 1990 concerned itself with studies of bird, murine and monkey plasmodia (Plasmodium lophurae, P. berghei and P. knowlesi) and this was summarized some 20 years ago (Sherman, 1979,1988). With the successful in vitro culture of P. falciparum, membrane-transport phenomena of malaria-infected red cells and free parasites have concerned themselves principally with this species and this too has been the subject of periodic review (e.g. see Kirk s tour de force, 2001). 

Since a malaria-infected red cell contains three membrane interfaces the plasma membrane of the red cell, the parasitophorous vacuolar membrane (PVM) and the parasite plasma membrane (PPM) studying membrane transport in such a system is not straightforward. Substrates have to traverse multiple membrane systems and a single membrane may contain multiple transporters for a particular substrate. To complicate the matter further, when we (and others) embarked on such studies not only were we usually unaware of the complexities of the transport systems that might be encountered, we were also unappreciative of the technical difficulties as well as possible artefacts that might result from isolating parasites and using heavy infections in unnatural hosts or from in vitro cultures. 

One of the earliest observations on transport was the movement of Na+ into the erythrocyte cytosol of malaria-infected red cells (Dunn, 1969 Overman, 1948 Overman et ah, 1949, 1950) yet until recently little was known about whether this was of any value to the intra-erythrocytic Plasmodium. In 2006, it was discovered that the parasite exploits not an H+-coupled transporter but a Na+ electrochemical gradient to energize the transporter for inorganic phosphate, an essential nutrient. The transporter was cloned, localized to the parasite surface and, when expressed in Xenopus oocytes, resulted in uptake properties similar to those of the parasite (Saliba et ah, 2006). 

Plasmodia were found to neither contain sialic acid nor were they capable of its synthesis (Schauer et al., 1984). Hence, when declines in sialic acid were found in P. berghei, P. knowlesi and P. yoelii it was assumed they were due to changes either in the quality or quantity of the host sialic acids (Howard and Day, 1981 Howard et ah, 1980,1986). It was claimed that the decreased reactivity of surface sialic acid for neuraminidase in murine and simian malaria-infected red cells was due to O-acetylation. However, they found little or no decrease in P. falciparum-infected red cells (Howard et al., 1981) and concluded that extensive removal or modification of sialic acid did not occur with human malaria, in contrast to the murine malaria. I believe their results can be explained quite simply the samples contained too few parasitized erythrocytes (i.e. parasitemias were low and most of the parasites were small, immature trophozoites). Indeed, when we re-investigated the sialic acids in P. lophurae-infected red cells where the parasitemias were above 80% (Sherman and Jones, 1979) there was a significant reduction (from 79 nmol/mg protein to 36 nmol/mg protein) and this was also found in in vitro grown P. falciparum (Sherman, personal communication) and P. vivax (reference in Sherman et al., 2004). Although we still do not understand the mechanism for loss of sialic acid from malaria-infected red cells I am of the opinion that the lowered amount of surface sialic acid is both real and significant. 

Sherman, I. W., and Jones, L. A. (1979). Plasmodium lophurae Membrane proteins of erythrocyte-free plasmodia and malaria-infected red cells. ]. Protozool. 26, 489-501. 

Manometric measures of intact infected red cells, parasites removed from infected cells by saponin or hemolytic serum or cell-free extracts showed that malaria parasites contained cytochromes and increased flavin adenine dinucleotide (FAD) levels (Ball et al., 1948). Ball et al. (1947)... 

Most of the glycolytic enzymes found in bird and simian malarias by standard biochemical assays have been found in P. falciparum-infected red cells (Roth et al., 1988) and increased enzyme activity is, in general, proportional to the parasitemia. By 2007, almost all of the genes for the glycolytic isoenzymes of P. falciparum had been cloned and sequenced (see http //sites.huji.ac.il/malaria/maps/glycolysispath.html last accessed 16 July 2008, and Woodrow and Krishna, 2005). 

A reduction in surface sialic acid would lower the overall surface charge on the infected red cell thereby decreasing the repulsive forces between cells and promoting adhesion (i.e. between trophozoite/schizont-infected red cells and endothelial cells). In addition, for those malarias in which glycophorin is a receptor (see p. 242 ) the reduced amounts of sialic acid could prevent merozoite invasion into a red cell already containing a growing parasite. 

An increase of vitamin C and E concentrations in P. vinckei-infected red cells led to the hypothesis that the parasites were able to synthesize these vitamins (quoted in Muller and Kappes, 2007), however, this is not supported by examination of the P. falciparum genome since genes for the synthesis of ascorbate or tocopherol were not found. A deficiency of vitamin C or E has a protective effect in malaria patients possibly because a lack of this anti-oxidant renders the parasites more vulnerable to oxidant stress. 

Cooke, B. M., Mohandas, N., and Coppel, R. L. (2001). The malaria-infected red blood cell Structural and functional changes. Adv. Parasitol. 50,1-86. 

Eda, S., and Sherman, I. W. (2002). Cytoadherence of malaria-infected red blood cells involves exposure of phosphatidylserine. Cell Physiol. Biochem. 12, 373-384. 

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