1998 Nature America Inc. • http://medicine.nature.com NEWS & VIEWS

Motherhood and malaria

Multigravid women, who are protected from malaria during pregnancy, possess antibodies that block the binding of infected erythrocytes to chondroitin sulfate A, a placental receptor.

OR CENTURIES, THE mortality in Africa from placentas contain infected red cells at Finfection with Plasmodium falciparum, LOUIS H. MILLER delivery. Fetal infections are rapidly elim- the causative organism of the most severe & JOSEPH D. SMITH inated without treatment4. form of malaria in humans, has equaled P. falciparum can be distinguished from mortality from all other causes. Chloro- their first pregnancy (primigravida), are other Plasmodium species that infect quine and other antimalarial drugs have an exception. Although they suffer from humans because only immature, ring- modified the terrible history of this dis- high parasitemias and anemia, the main infected erythrocytic forms circulate in ease, but recently, with the spread of drug effect of infection is on the fetus and the the peripheral blood. Mature erythrocytic resistance, death from malaria has risen newborn infant. Infected mothers have forms (trophozoites and schizonts) bind dramatically. The new Director General of low birthweight babies who have an to vascular endothelium through ’knobs’ the World Health Organization, Gro increased risk of dying4. The deleterious (parasite-induced modifications of the red Harlem Brundtland, has responded appro- effects of malaria on fetal development are cell surface) that enable them to be priately to this emergency with a new pro- believed to stem from the large numbers sequestered in the venules and to avoid gram called Roll Back Malaria, which seeks of infected erythrocytes sequestered on elimination by the spleen. Assays to detect to halve malaria-induced mortality by the the maternal side of the placenta. Ordi- binding of infected red cells to endothe- year 2010. One component of this pro- narily, the maternal and fetal circulations lium were developed in the early 1980s gram is the search for new drugs, vaccines do not mix, but infection of infant cord and have helped to define several differ- (none exist today) and other tools to blood is more common in mothers whose ent receptors including CD36, throm- reduce disease and mitigate the cost of bospondin, intracellular adhesion mol- malaria control. Umbilical cord ecule 1 (ICAM1) and others3. A scientific correspondence in Nature During the search for new receptors, by Fried et al.1 describes a finding that infected erythrocytes were found to raises the possibility of a vaccine to bind to CSA (refs. 5,6). Although CD36 http://medicine.nature.com reduce the complications from malaria is considered the main receptor for the • during pregnancy. For a long time it has adherence of parasitized red cells to been known that such complications venular endothelium, parasites recov- are less frequent in women who have ered from the placenta strongly adhere had multiple pregnancies (multi- Maternal to CSA but not to CD36 (ref. 7, and J. gravid). Fried and colleagues report that Intervillous Space Beeson & S. Rogerson, personal com- multigravid women possess antibodies munication). These findings begin to Fetal Villous that block infected erythrocytes from Space unravel the mystery of the mechanism binding to chondroitin sulfate A (chon- by which parasites sequester them- 1998 Nature America Inc. 1998 Nature droitin-4-sulfate, CSA), a receptor that selves in the placenta. Maternal blood enables the parasites to sequester them- empties into the placental intervillous selves in the placenta. Sera from multi- space that is lined with syncytiotro- gravid Kenyan women blocked adhe- phoblasts (see Fig.). Whereas the para- sion of infected erythrocytes from sitized erythrocytes adhering to pregnant women in different parts of venules contain ‘knobs’ that are in the world suggesting that the antibod- close apposition to the endothelial sur- Syncytiotrophoblast Parasitized ies may be strain-independent. Erythrocytes face, ultrastructural analysis of the pla- Malaria in Africa is not a single dis- centa shows that the ‘knobs’ of ease. Unlike non-immune individuals Characteristics of the mature placenta. Maternal blood infected red cells are not closely associ- from Europe and the United States in empties into the intervillous space and flows over ated with syncytiotrophoblasts. whom the first infection can be lethal, syncytiotrophoblasts that line chorionic villi extensions Indeed, parasitized erythrocytes in the from the fetus. Fetal blood vessels are contained within many early infections in African chil- intervillous space do not seem to make the villi. The photograph (by Daniel Connor) shows a dren are not severe. There is an age placenta containing P. falciparum-infected erythrocytes . close contact with syncytiotro- dependency for disease complica- Infection is confined to maternal erythrocytes in the phoblasts. The syncytiotrophoblast tions2,3: severe anemia occurs early in intervillous space and is absent in fetal erythrocytes surface bears the proteoglycan throm- childhood; cerebral malaria, later. After within the villi. Infected erythrocytes recovered from bomodulin and perhaps other proteo- repeated infections, children develop placenta bind CSA and adhere to syncytiotrophoblasts glycans such as betaglycan that display anti-malarial immunity that controls possibly through thrombomodulin, a proteoglycan that CSA. Infected red cells adhere to parasite growth and limits disease from bears CSA. Many infected erythrocytes in the intervillous thrombomodulin in vitro, so it is possi- space do not seem to make close contact with subsequent infections. Adults living in ble that CSA on this proteoglycan, syncytiotrophoblasts. Women who have antibodies that endemic regions rarely experience block infected erythrocyte adherence to CSA have fewer extending well beyond the syncy- severe malaria morbidity. However, parasites in the placenta at delivery than women tiotrophoblast surface, binds infected pregnant women, especially those in without these blocking antibodies. red cells.

1244 NATURE MEDICINE • VOLUME 4 • NUMBER 11 • NOVEMBER 1998 1998 Nature America Inc. • http://medicine.nature.com NEWS & VIEWS

The best-characterized parasite adhe- adhesion of a special placental subset of focus vaccine development against P. fal- sion molecules belong to the PfEMP1 (P. CSA-binding parasites. ciparum. falciparum erythrocyte membrane protein In their study, Fried and co-workers1 1) family of proteins, which are encoded assessed the ability of sera from individuals Acknowledgement by var genes8–10. PfEMP1 proteins are con- living in Kenya, Malawi and Thailand to We thank J. Gysin and S. Rogerson for suggestions. centrated in the ‘knobs’ of infected ery- inhibit binding of parasitized red cells to 1. Fried, M., Duffy, P.E., Nosten, F., Brockman, A. & throcytes and bind CD36 (ref. 8). There CSA. Anti-CSA adhesion activity was pre- Brabin B.J. Pregnant women block malaria parasite are about 50 copies of the var gene per sent in multigravid women who had few binding. Nature (in the press). genome and a different set of var genes in sequestered parasitized red cells in their 2. Marsh, K. Malaria—a neglected disease? Parasitology 104, Suppl. S53–S69 (1992). 9 each P. falciparum clone . Thus, there is a placentas, but was absent in primigravid 3. Miller, L.H., Good, M.F. & Milon, G. Malaria patho- large repertoire of adhesion molecules women and adult Kenyan males. Multi- genesis. Science 264, 1878–1883 (1994). 4. Steketee, R.W. et al. The problem of malaria and available to the parasite. Antibodies to one gravid Kenyan women, especially from malaria control in pregnancy in sub-saharan Africa. PfEMP1 variant kill infected erythrocytes high transmission areas, have anti-CSA Am. J. Trop. Med. Hyg. 55, 2–7 (1996). that express this variant. Unfortunately, antibodies that are strain-independent; 5. Rogerson, S.J., Chaiyaroj, S.C., Ng, K., Reeder, J.C. & Brown, G.V. Chondroitin sulfate A is a cell surface the malaria parasites constantly switch that is, they block CSA binding of placen- receptor for Plasmodium falciparum-infected ery- expression to other versions of PfEMP1. If tal parasites collected from pregnant throcytes. J. Exp. Med. 182, 15–20 (1995). the immune system has not experienced a women from Asia and other parts of Africa. 6. Robert, C. et al. Chondroitin-4-sulphate (proteogly- can), a receptor for Plasmodium falciparum-infected particular PfEMP1, then parasite clones The essential question is whether anti-CSA erythrocyte adherence on brain microvascular en- expressing this variant are able to expand. antibodies are directed at a conserved dothelial cells. Res. Immunol. 146, 383–393 (1995). 7. Fried, M. & Duffy, P.E. Adherence of Plasmodium fal- During the course of P. falciparum infec- region present on all parasites sequestered ciparum to chondroitin sulfate A in the human pla- tion, children develop antibodies against in the placenta or whether antibodies have centa. Science 272, 1502–1504 (1996). the variant antigens of the infecting iso- multiple specificities. Two independent 8. Baruch, D.I. et al. Cloning the P. falciparum gene en- 11 coding PfEMP1, a malarial variant antigen and ad- late . Presumably, sufficient immunity studies have shown that in vitro selection herence receptor on the surface of parasitized eventually develops to the full PfEMP1 of infected erythrocytes on CSA leads to human erythrocytes. Cell 82, 77–87 (1995). repertoire to maintain infections at low enrichment of single var mRNAs encoding 9. Su, X.-Z. et al. The large diverse gene family var en- codes proteins involved in cytoadherence and anti- parasitemias; disease develops in children PfEMP1 (refs. 12,13). It is unknown genic variation of Plasmodium falciparum-infected who lack a full range of antibodies11. whether parasites in the placenta bind to erythrocytes. Cell 82, 89–100 (1995). 10. Smith, J.D. et al. Switches in expression of Why then during the first pregnancy do CSA through PfEMP1 or some other lig- Plasmodium falciparum var genes correlate with women develop high parasitemias that are and. If antibodies from pregnant women changes in antigenic and cytoadherent phenotypes http://medicine.nature.com not seen in these same women before recognize a conserved epitope, then the of infected erythrocytes. Cell 82, 101–110 (1995). • 11. Bull, P.C. et al. Parasite antigens on the infected red pregnancy? It now seems that the pla- CSA-binding domain of the parasite— cell are targets for naturally acquired immunity to centa may provide a new haven, selecting whether it be in PfEMP1 or some other malaria. Nature Med. 4, 358–360 (1998). for CSA-binding parasites. Infected red molecule—becomes a potential target for 12. Scherf, A. et al. Antigenic variation in malaria: in situ switching, relaxed and mutually exclusive transcrip- cells that bind CSA are rare in non-preg- vaccine development. Definition of the tion of var genes during intra-erythrocytic develop- nant adults despite the fact that thrombo- parasite CSA-binding domain will permit ment in Plasmodium falciparum. EMBO J. 17, 5418–5426 (1998). modulin is present on vascular endothe- more detailed characterization of the con- 13. Reeder, A.J. et al. Identification of a var gene associ- lium. The precise chemistry of CSA in the servation of this region in parasites ated with the adherence of Plasmodium falciparum placenta is unknown, but differences sequestered in the placenta. to chondroitin sulfate. Molecular Parasitology Meeting VIII, 1997 (abstract). 1998 Nature America Inc. 1998 Nature between endothelial and placental CSA The usefulness of PfEMP1 and other par- may explain parasite adhesion in the pla- asite adhesion molecules as vaccine can- centa and the distance of infected red cells didates has been questioned because they Laboratory of Parasitic Diseases from syncytiotrophoblasts. Furthermore, are so highly variable. The Fried study NIAID, NIH blood flow within the intervillous space is demonstrates how insights into the Bethesda, Maryland 20892-0425, USA extremely slow and this might facilitate pathogenesis of malaria may inform and e-mail: [email protected] A happier sequel to Lorenzo’s Oil?

Pharmacological manipulation of gene expression brings new hope to the treatment of X-linked adrenoleukodystrophy (pages 1261–1268).

UCH IS KNOWN about the biochemical ease. This is the approach taken by Mand genetic bases of inherited diseases RONALD J. A. WANDERS Kemp et al.3, as reported on page 1261 of this in man, but there has been less progress in issue, in the treatment of X-linked the development of suitable therapies. For the treatment of tyrosinemia type I (ref. 1). adrenoleukodystrophy (X-ALD), a disease some inborn errors of metabolism treat- In other disorders, treatment aims to cor- made famous by the movie Lorenzo’s Oil. ment relies on restricted dietary intake of rect the primary defect directly—a good The investigators show that the drug 4- certain food components (for example, example is the administration of gluco- phenylbutyrate (4PBA) promotes the phenylketonuria) whereas in others, ther- cerebrosidase to Gaucher disease patients2. expression of a peroxisomal protein (func- apy of any sort is non-existent. Pharmaco- Another strategy uses drugs to increase the tionally related to the defective peroxiso- logically preventing the formation of a expression of a gene that is functionally mal protein in X-ALD), which corrects the harmful compound has shown promise in related to the defective gene causing the dis- metabolism of very-long-chain fatty acids

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