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Infectious Diseases in an Age of Change: The Impact of Human Ecology and Behaviour on Disease Transmission Impact of Malaria on Genetic Polymorphism and Genetic Diseases in Africans and African Americans LOUIS H. MILLER Africa is the area of the world most threatened by malaria because it has the most efficient mosquito vectors, the Anopheles gambiae complex. Outside the endemic areas of Africa, An. Gambiae has caused some of the worst epidemics of our century. One such malaria epidemic occurred when An. gambiae was introduced into Brazil. The effects in Africa are more insidious, in that malaria kills young children and pregnant women; adults are immune and little affected. The problem has been compounded by the spread of chloroquine resistance. This has threatened the availability of the cheapest and safest treatment to diminish the impact of malaria in these areas where mosquito control has been ineffective. The combination of sulfadoxine and pyrimethamine is a temporary stopgap. Cost is a major consideration in poor countries and will limit the availability of newer drugs. In Asia and Brazil, where the population can afford more expensive drugs, resistance to these drugs has developed. The development of malaria vaccines, which will reduce mortality and the spread of drug-resistant malaria, has not received the necessary funding or industrial interest to be successful within a reasonable period of time. The crisis in development of new modalities against malaria is made worse by the minimal industrial interest in antimalarial drug development. Louis H. Miller is chief, Laboratory of Malaria Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
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Infectious Diseases in an Age of Change: The Impact of Human Ecology and Behaviour on Disease Transmission ESTIMATES OF MORTALITY FROM MALARIA What will be the impact of parasite resistance to antimalarial drugs on death in the population? Malaria is one of the few diseases for which we can predict the impact of the loss of drugs without an alternative form of control. We obtain these estimates of past and future malarial mortality from the frequencies of certain genes observed today. J. B. S. Haldane (1) was the first to propose that infectious diseases were the main selective force for human evolution during the past 5000 years. In a recent study of diversity at the molecular level, Murphy (2) compared sequences of genes common between rodents and humans. It was found that host defense genes were more diverse than all other classes of proteins, suggesting that selection in mice and humans resulted from exposure to different microorganisms. In Europeans, tuberculosis has been a major selective force in evolution; in Africans, malaria was one of the major selective forces in their evolution and, as a result, many genes are known to confer a survival advantage. One of the best studied is the gene for hemoglobin S. From the frequency of the gene for hemoglobin S, it is possible to estimate the mortality from malaria by using the Hardy–Weinberg equation (3). It is assumed that mortality from malaria is the sole selective force for the gene. The mortality of hemoglobin SS in West Africa is 100% in childhood. In malaria-endemic areas, SA heterozygotes have a survival advantage compared with hemoglobin AA children. This selection of a deleterious gene by survival advantage for another disease (e.g., malaria) is referred to as a balanced polymorphism. In some areas of Africa, the mortality from malaria must have been as high as 25% to account for the hemoglobin S gene frequencies that we see today. Another example of balanced polymorphism is a mutation in erythrocyte band 3, which causes a certain form of erythrocyte membrane defect known as Melanesian ovalocytosis. This mutation is a 27-base-pair (9 amino acid) deletion in band 3 (4). It is particularly common in Papua New Guinea, the only other area of the world with transmission of malaria to equal that seen in Africa. The ovalocytic erythrocyte is partially resistant to invasion by malaria parasites. Homozygosity for this mutation is 100% lethal during fetal development, the price that is paid for a deleterious gene that helps survival in heterozygous children. The broader implications of the above studies are as follows. (i) Definitive studies on the population genetics of this disease were impossible before identification of the genetic defect because there are a number of causes of abnormally shaped erythrocytes in Papua New Guinea. It only now has been possible to study its gene frequency and the impact of the mutant allele on intrauterine lethality of the homozygote.
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Infectious Diseases in an Age of Change: The Impact of Human Ecology and Behaviour on Disease Transmission (ii) The fact that the gene frequency—like that of hemoglobin S in Africa—is high argues for a high mortality from malaria in Papua New Guinea. Although high mortality is not seen today because of chloroquine, it may be a problem in the future when antimalarial drugs become ineffective. (iii) Why have band 3 mutations in Papua New Guinea never occurred in Africa, and why has hemoglobin S never occurred in Papua New Guinea? Other erythrocyte skeletal mutations have been identified in Africa that appear to affect parasite development (5, 6). (iv) Despite the slow evolution of the human genome compared to that of the parasite, the host innate resistance mechanisms can afford improved survival. It may not be in the best interest of the parasite to kill its host. The fact that certain polymorphisms such as hemoglobinopathies and glucose-6-phosphate dehydrogenase deficiency were selected for by malaria is well known (7, 8). I am going to explore other genetic differences that exist between Africans and Caucasians that may have been selected for by malaria and what clues they may provide for drug and vaccine development. Some of these polymorphisms are deleterious; genetic markers for these would identify individuals at risk for preventive therapy. Others are neutral as far as we know and have gone to fixation at 100%. HYPERTENSION AND IRON OVERLOAD Hypertension and liver disease are two major diseases that affect African Americans at a higher frequency than European Americans. Because the genetic bases are unknown, the potential that these genes confer resistance to malaria should be considered. There are many hypotheses for the selective force that led to the increased incidence of hypertension in African Americans. Theories postulate that African Americans, who retain salt more avidly than European Americans, were selected for because of limited availability of salt in Africa, death during the transportation of slaves from Africa to America, or death during subsequent life as a slave in America. The validity of these hypotheses has been questioned by historian Philip Curtin (9). He pointed out that most slaves lived within 100 miles of the African coast where there was a readily available, inexpensive source of salt from evaporation of sea water. He also examined the causes of death in slaves and found no evidence for an excess of diseases related to salt loss. I would like to raise the possibility that differences in salt metabolism, especially as they may be reflected in erythrocytes, may have been selected by malaria. The erythrocytes of African Americans are known
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Infectious Diseases in an Age of Change: The Impact of Human Ecology and Behaviour on Disease Transmission to have higher sodium, lower potassium, and altered sodium transport when compared to European Americans (10, 11). The potential connection may relate to the fact that there are no malarias of animals that have high-sodium erythrocytes such as dogs, cats, cows, and horses. There are saurine malarias, rodent malarias, avian malarias, and primate malarias, all in animals that have high-potassium erythrocytes (12). The absence of malaria in dogs and cows is not likely to have been related to an absence of opportunity for infection because of lack of receptors for cell invasion. This requirement for K+ was consistent with the finding of Trager et al. (13) that asexual erythrocytic malaria parasites required a high K+ culture medium when the parasites were grown outside of erythrocytes (13). The exact definition of how potassium affects parasite growth is complicated by the fact that the parasite grows at a normal rate in erythrocytes treated with ouabain, which increases intraerythrocytic sodium and decreases intraerythrocytic potassium (14, 15). It is possible that the shift in sodium/potassium may reduce parasite growth through a third factor such as hemoglobin S or that other ouabain-insensitive transporters may affect parasite growth. How this may affect the intraerythrocytic parasite derives in part from the work of Friedman (16) on growth of Plasmodium falciparum in hemoglobin SA erythrocytes (16). He found that the parasite growth in hemoglobin SA erythrocytes was normal under an atmosphere of 17% O2, but the parasites could not grow at 3% O2. The parasites could, however, grow normally in SA hemoglobin at 3% O2 tension if the culture medium contained high K+ concentrations. The parasitized erythrocytes grown in the usual culture medium at low oxygen tension sickled and lost K+. The parasitized erythrocytes still sickled in high K+ medium, but the erythrocyte K+ remained normal. The question of whether hypertension genes suppress the growth of the malaria parasite and give a survival advantage in malariaendemic areas cannot be studied until the molecular basis of hypertension and the differences in erythrocyte sodium in Africans and African Americans have been identified. Genetic markers would also identify those at risk of hypertension and may suggest drugs or dietary precautions to prevent this common disease. Mutations in the angiotensinogen gene have been associated with hypertension in Caucasians (17), but its involvement in hypertension in African Americans remains undefined. Iron overload and concomitant liver disease in sub-Sahara Africa have only recently been shown to have a genetic basis (18). Large deposits of hemosiderin are found in the Kupffer cells and hepatic parenchymal cells and are associated with portal fibrosis and cirrhosis. Diabetes mellitus may also occur at increased frequency in these patients because
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Infectious Diseases in an Age of Change: The Impact of Human Ecology and Behaviour on Disease Transmission of similar hemosiderin deposits in the pancreas. Recently, Gordeuk et al. (18) demonstrated that the disease is genetic; however, unlike hereditary hemochromatosis of Caucasians, the disease is not linked to the HLA locus. In Southern Africa, the disease is associated with a high intake of beer brewed in steel drums, and it is proposed that the disease results from an interaction of genetic susceptibility and the intake of excessive iron and alcohol. Why would I speculate that the gene responsible for this disease was selected for by increased fitness in a malaria-endemic area? How could abnormalities in iron metabolism be involved in resistance to malaria when the parasite has a ready supply of iron from digestion of hemoglobin, a main source of amino acids for the parasite? Iron in the form of ferriprotoporphyrin IX is highly toxic to the parasite. The parasite detoxifies iron by forming malaria pigment, a form that is inaccessible to the parasite. Malaria pigment is β-hematin (19) that can be formed in the test tube from polymerization of ferriprotoporphyrin IX at pH 3 and high temperatures. In the cell, however, formation of β-hematin requires a polymerase, an enzymatic activity that was discovered by Slater and Cerami (20). Interestingly, polymerization is inhibited by chloroquine and other active 4-aminoquinolines (20), solving the mystery of the mode of chloroquine action. It has been further shown, through studies with iron chelation by desferroxamine, that the malaria parasite must obtain iron from the outside by unknown mechanisms (21). Iron uptake by the parasite may require a ferric reductase, a receptor, and a transporter molecule. If altered iron metabolism is proven to confer resistance to malaria, it would be an impetus to explore iron-related pathways in malaria therapy. In addition, this African disease may cause increased liver disease in African Americans. The study of these questions would require identification of the genetic basis of iron overload and the determination of whether this gene is associated with increased resistance to malaria in Africa and liver disease in African Americans. It is clear that hypertension and iron overload in Africans and African Americans may be preventable by diet, and the search for its genetic basis deserves high priority to develop molecular probes to identify those at risk. HLA AND MALARIA Piazza et al. (22) were the first to present evidence of the association between HLA and malaria from gene frequencies in Sardinia, comparing lowland areas where malaria occurred and highland areas (22). In the definitive studies by Hill et al. (23), a class I molecule, HLA-B53, was found in lower frequency in Gambian children with severe malaria than in the general population. Class I molecules contain a groove that
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Infectious Diseases in an Age of Change: The Impact of Human Ecology and Behaviour on Disease Transmission presents antigen to the T-cell receptor on CD8+ T cell.s Antigens presented in this way are targets for CD8+ T-cell-dependent cytotoxicity. What cells in the malaria life cycle can present antigens through the HLA class I pathway? Sporozoites injected into humans invade the liver parenchymal cells, where they multiply. Liver parenchymal cells express class I HLA antigens and, theoretically, could present malarial antigens to CD8+ T cells. Merozoites released from liver cells invade erythrocytes, thereby initiating the erythrocytic stage in the life cycle that causes disease. There is no evidence in rodent malarias that CD8+ T cells are critical for immunity to the erythrocytic stage. Immunity to the liver stage has been shown to be dependent in part on CD8+ T cells (24, 25). For example, immunity induced by irradiated sporozoites was eliminated by CD8+ T-cell depletion. Subsequently, the CD8+ T-cell epitope on the CS protein was identified in P. falciparum (26, 27). Of great concern when this epitope was identified was the fact that it was highly variant among clones of P. falciparum. The strategy used by Hill et al. (28) for identifying malaria epitopes presented by HLA-B53 to CD8+ T cells was as follows. The peptide presented by HLA-class I molecules usually consists of eight or nine amino acids, depending on the class I molecule. The peptides eluted from the groove were sequenced, and from this information the invariant anchor amino acid, proline, at position 2 of the nonapeptides, was identified. All possible nonapeptides with a proline at position 2 from the four malaria proteins of the sporozoite and liver stages were synthesized. These were tested as targets of cytotoxicity with cells from immune, adult Gambians who were HLA-B53 (28). A peptide from one of the liver-stage antigens was identified that was a target of cytotoxic CD8+ T cells. This must undergo testing as a potential antigen to induce CD8+ T-cell-mediated immunity. There is one curiosity of this immunity. Although the severity of illness was less in children who expressed HLA-B53 than those who did not, the incidence of blood-stage infections was not reduced (23). How HLA-B53 could protect without reducing infection rates probably reflects our limited understanding of pathogenesis in malaria. A potential parallel may be drawn with protection against malaria by permethrin-impregnated bed nets, which reduced mortality in the age group 1–5 years (29). Curiously, the infection rate in the children protected by the impregnated bed nets was as high as in the unprotected community. One speculation is that a reduced number of clones inoculated into a child might reduce the child's risk of being exposed to a clone that is antigenically unique. Thus, either bed nets or a certain HLA type may give enough protection to decrease the number of parasite clones infecting a child and, in this way, may lead to increased survival. It is evident that such results may
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Infectious Diseases in an Age of Change: The Impact of Human Ecology and Behaviour on Disease Transmission TABLE 1 Blood group antigens of African origin Blood group African European Comment Ref(s). Duffy negative [Fy(a- b-)] ≈100% (W. Africa) 0% Chemokine receptor; P. vivax receptor 30, 31, 32, 33 Glycophorin Dantu 4% 0% P. falciparum receptor; hybrid glycophorin (extracellular glycophorin B, transmembrane and cytoplasmic glycophorin A) 34 Glycophorin B negative (S- s- U-) 20% (Pygmies) 0% P. falciparum receptor 35 Sl(a-) 30% (in USA) 1% Polymorphism in complement receptor 1 (CR1) 36, 37 Rh (V+) 40% 0% 13 transmembrane loops (function unknown) 38, 39 Jsa 17% (in USA) 1% Zinc metalloendopeptidase-like 40, 41 change our strategy for vaccine development in endemic areas where improved survival is the goal. BLOOD GROUPS AND MALARIA There are blood group differences between African Americans and Caucasian populations (Table 1). Sl(a-), which is found in 50% of African Americans, is rare in Caucasian populations. Sl(a-) is a polymorphism in the erythrocyte CR 1 receptor for C3b/C4b (36). It is thought that this receptor is involved in clearing immune complexes from the circulation and may be related to the 4-fold increase in systemic lupus in African Americans. We have been unable to find any reduced invasion of these erythrocytes. Although I still believe it was selected by malaria, I have been unable to find the connection. Africans also have a high frequency of Rh and Kell antigens that differ from those found in Caucasians (38, 40). One of the genes encoding Rh has recently been cloned, and it is predicted to cross the membrane 13 times (39). Although the function of Rh remains a mystery, it is possible that it may be involved in membrane transport or membrane integrity and may affect survival of the intraerythrocytic parasite. From the parasite's point of view, certain blood group antigens on the erythrocyte surface are receptors for the attachment and invasion of the erythrocyte. Mutations in these surface proteins in Africans were selected for by resistance to invasion of erythrocytes by malaria parasites.
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Infectious Diseases in an Age of Change: The Impact of Human Ecology and Behaviour on Disease Transmission Invasion consists of multiple steps that include initial recognition, reorientation to bring the apical end of the parasite in contact with the erythrocyte, junction formation, and entry into a vacuole created by the parasite (42). There are multiple receptors involved in these steps (43). This derives from the finding that Africans are unable to be infected with Plasmodium vivax because almost 100% lack the Duffy blood group antigens (30, 31). Knowledge of the requirements of P. vivax for invasion derive largely from studies on the interaction between Duffy-negative erythrocytes and Plasmodium knowlesi, a simian malaria that also requires the Duffy blood group system to invade human erythrocytes. The parasite attaches and apically reorients on Duffy-negative erythrocytes but cannot form a junction or invade these erythrocytes (44). Thus, the initial receptors involved in attachment are unrelated to Duffy blood group antigens. It is only at the stage of junction formation that the Duffy blood group system is involved as a receptor. The Duffy blood group system has now been shown to be the erythrocyte chemokine receptor (32, 33). Chemokines are a family of molecules involved in chemotaxis and proinflammatory activities related to activating cells like neutrophils for chemotaxis and for binding endothelium. The erythrocyte chemokine receptor, when originally identified, was proposed to be a scavenger for inflammatory mediators (45). If this hypothesis is correct, then there should be physiologic differences between Duffy-positive and -negative individuals. It has been observed that Africans and African Americans have a lower peripheral neutrophil count (46), although this is not associated with increased susceptibility to infection. The question of whether this lower neutrophil count is causally related to Duffy negativity remains to be determined. The involvement of Duffy antigens in chemokine metabolism also raises the question of whether Duffy negativity in West Africa provides a survival advantage in terms of the ability to control P. falciparum infections. The absence of the receptor for P. vivax may have been a by-product of this other selective advantage. Alternatively, resistance to P. vivax may have selected for Duffy negativity. Investigation into genetically determined resistance to P. vivax led to discoveries of Duffy antigens as the erythrocyte chemokine receptor. This, in turn, suggested new approaches to drug therapy and vaccine development. Chemokines block invasion by P. knowlesi (32) and would presumably also block P. vivax. The possibility now exists that chemokine analogs can be developed as antimalarial therapy through receptor blockade. The parasite molecule that binds to Duffy antigens may provide an effective vaccine, as antibodies against the molecule may inhibit invasion. We have recently succeeded in identifying the domain of the
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Infectious Diseases in an Age of Change: The Impact of Human Ecology and Behaviour on Disease Transmission parasite Duffy binding ligand, which binds Duffy-positive but not Duffy-negative erythrocytes (47). Each region of the extracellular portion of the molecule was expressed in COS cells, and only region II bound. The Duffy binding molecule of P. vivax has structural and sequence homology with a sialic acid binding molecule of P. falciparum (48). The same domain in the P. falciparum ligand was shown to bind human erythrocytes in a sialic acid-dependent manner (49). That is, neuraminidase-treated human erythrocytes could not bind COS cells expressing P. falciparum region II. An erythrocyte mutant that lacks glycophorin A, En(a-) erythrocytes, also did not bind to these COS cells. This result suggests that glycophorin B, the second most common sialoglycoprotein on the erythrocyte surface, cannot act as receptor for this parasite ligand. Consistent with this finding was the fact that trypsin-treated erythrocytes that lack glycophorin A, but not glycophorin B, could not bind to the region II-expressing COS cells. The first 25 amino acids of glycophorins A and B are identical and contain most of the sialic acid residues (50). One difference between glycophorins A and B is that glycophorin A, and not B, has one N-linked oligosaccharide. This difference in N-linked oligosaccharides is unlikely to explain the differential binding of glycophorin A, as O-Glycanase but not N-Glycanase treatment of erythrocytes rendered them refractory to binding of the P. falciparum sialic acid binding ligand (49). The basis of specificity of glycophorin A as a receptor for EBA-175 was tested in two ways (49). First, glycophorin A, but not glycophorin B, inhibited erythrocyte binding to COS cells expressing the binding domain of EBA-175. Second, glycophorin A or the N-terminal 64 amino acids of glycophorin A blocked binding of EBA-175 to erythrocytes; shorter N-terminal peptides that contain most O-linked oligosaccharide and the one N-linked oligosaccharide did not block attachment. These data demonstrate that EBA-175 binds specifically to glycophorin A and that the binding is dependent on sialic acid and the peptide backbone. It is unknown whether the peptide acts to present clusters of sialic acid in a specific spatial distribution or whether it functions as part of the receptor. P. falciparum, unlike P. vivax, has developed alternative pathways for invasion. Thus, deletion of a receptor does not appear to make the population completely resistant to P. falciparum. In fact, we and others have developed data for multiple alternative pathways for invasion (51–53). One of the pathways uses glycophorin B with a different parasite ligand (54). Although there is evidence that both glycophorin A and B are used as receptors for P. falciparum, the abnormalities in the population are all in glycophorin B (55–57). Glycophorin B negative erythrocytes in some pygmy populations reach frequencies of 20%. The mutation in glycophorin
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Infectious Diseases in an Age of Change: The Impact of Human Ecology and Behaviour on Disease Transmission B and the relative severity of P. falciparum in glycophorin B negative pygmies has yet to be studied. If this was selected by P. falciparum, which seems likely, then the parasite is unable to produce full virulence in these individuals. Multiple other mutations of glycophorin B in Africans have been observed, such as Dantu, Henshaw and U-. Dantu results from a recombination between the glycophorin A gene and the glycophorin B gene, which leads to a mutant that has part of the extracellular domain of glycophorin B and the transmembrane and cytoplasmic domains of glycophorin A. Dantu also has a normal copy of glycophorin A and lacks glycophorin B. Henshaw has point mutations in the N-terminus of glycophorin B that influences antigenicity and probably folding in other regions of the molecule. In Southeast Asia, another area of severe P. falciparum malaria, Miltenburger III occurs at high frequencies. Like Dantu, Miltenberger III involves a recombination between glycophorin A and B and also has a normal glycophorin A allele; the normal glycophorin B allele is missing. We can conclude that either deficiency of glycophorin A gives no selective advantage or that glycophorin A deficiency is detrimental. It is known that individuals with En(a-) erythrocytes that lack glycophorin A appear to have no associated disease. Perhaps in Africa, however, this gene deletion is more deleterious. Alternatively, in the setting of glycophorin B mutations, but not of glycophorin A mutations, the parasite is unable to express its full virulence, and consequently mutations in glycophorin B are selected. As a correlary, vaccines against the parasite ligand that binds glycophorin B may be a better target than EBA-175, the ligand for glycophorin A. It is clear that, despite these mutations in glycophorin B, the parasite remains in the population and is able to invade erythrocytes with these mutations. When P. vivax lacks this flexibility is unknown, but such flexibility is clearly an advantage for the parasite that can respond to polymorphisms in the human population. Malaria is a major cause of mortality and, as a consequence, it has had a marked and varied impact on the genetic makeup of the human population. It should be equally clear why there is a need to invest in the discovery of alternative methods of malaria control such as vaccines and approaches to modifying the vector population. We have a few years before the antimalarial drugs become unacceptably expensive for the poor countries. It is during this precious time that we must search for alternatives to reduce mortality. Unfortunately, obtaining the resources and industrial support for vaccine development has been difficult for this disease, which little affects our lives in the wealthy countries. It is a challenge to all of us in the world community to accelerate development of methods to reduce the impact of malaria.
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Infectious Diseases in an Age of Change: The Impact of Human Ecology and Behaviour on Disease Transmission Summary The high mortality from malaria in sub-Sahara Africa selected multiple genes that give the population a selective advantage. Identification of the genetic basis for resistance may suggest unusual approaches to development of malarial vaccines and antimalarial drugs. Some of these genes may be deleterious, although of selective advantage within the African setting, and need to be identified for counseling for disease prevention. I thank Dr. Victor Gordeuk (George Washington University) for sharing unpublished data on iron metabolism, Dr. Jiri Palek (St. Elizabeth's Hospital, Boston) for sharing unpublished data on ovalocytosis, Mary McGinniss for discussions on blood groups, and Dr. Terrence Hadley for general discussion of the paper. References 1. Haldane, J. B. S. (1949) Ric. Sci. Suppl. 19, 68–76. 2. Murphy, P. (1993) Cell 72, 823–826. 3. Smith, S. M. (1954) Ann. Hum. Genet. 19, 51–57. 4. Jarolim, P., Palek, J., Amato, D., Hassan, K., Sapak, P., Nurse, G. T., Rubin, H. L., Zhai, S., Sahr, K. E. & Liu, S.-C. (1991) Proc. Natl. Acad. Sci. USA 88, 11022–11026. 5. Lecomte, M.-C., Chermy, D., Solis, C., Ester, A., Féo, C., Gautero, H., Bournier, O. & Boivin, P. (1985) Blood 65, 1208–1217. 6. Facer, C. A. (1986) Int. Symp. Malaria (Memorias do Instituto Oswaldo Cruz, Rio de Janiero, Brazil), Vol. 81, pp. 111–114. 7. Nagel, R. L. (1990) Blood Cells (Springer, New York), Vol. 16, pp. 321–339. 8. Yuthavong, Y. & Wilairat, P. (1993) Parasitol. Today 9, 241–245. 9. Curtin, P. D. (1992) Am. J. Public Health 82, 1681–1686. 10. Canessa, M., Adragna, N., Solomon, H. S., Connolly, T. M. & Tosteson, D. C. (1980) N. Engl. J. Med. 302, 772–776. 11. Canessa, M., Lâski, C. & Falkner, B. (1990) Hypertension 16, 508–514. 12. Garnham, P. C. C. (1966) Malaria Parasites and Other Haemosporidia (Blackwell, Oxford). 13. Trager, W., Langreth, S. G. & Platzer, E. G. (1972) Proc. Helminthol. Soc. Wash. 39, 220–230. 14. Ginsburg, H., Handell, S., Friedman, S., Gorodetsky, R. & Krugliak, M. (1986) Z. Parasitenkd. 72, 185–199. 15. Tanabe, K., Izumo, A. & Kageyama, K. (1986) Am. J. Trop. Med. Hyg. 35, 476–478. 16. Friedman, M. J. (1978) Proc. Natl. Acad. Sci. USA 75, 1994–1997. 17. Jeunemaitre, X., Sourbier, F., Kotelevtsev, Y. V., Lifton, R. P., Williams, C. S., Charru, A., Hunt, S. C., Hopkins, P. N., Williams, R. R., Lalouel, J.-M. & Corvol, P. (1992) Cell 71, 169–180. 18. Gordeuk, V., Mukiibi, J., Hasstedt, S. J., Samowitz, W., Edwards, C. Q.,
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Representative terms from entire chapter: