Coevoultionary genetics of Plasmodium malaria parasites and their human hosts

Coevoultionary genetics of Plasmodium malaria parasites and their human hosts

Evans, Andrew G

Coevolutionary Genetics of Plasmodium Malaria Parasites and Their Human Hosts1

SYNOPSIS. Malaria has been invoked, perhaps more than any other infectious disease, as a force for the selection of human genetic polymorphisms. Evidence for genome-shaping interactions can be found in the geographic and ethnic distributions of the hemoglobins, blood group antigens, thalassemias, red cell membrane molecules, human lymphocyte antigen (HLA) classes, and cytokines. Human immune responses and genetic variations can correspondingly influence the structure and polymorphisms of Plasmodium populations, notably in genes that affect the success and virulence of infection. In Africa, where the burden from Plasmodium falciparum predominates, disease severity and manifestations vary in prevalence among human populations. The evolutionary history and spread of Plasmodium species inform our assessment of malaria as a selective force. Longstanding host-pathogen relationships, as well as recent changes in this dynamic, illustrate the selective pressures human and Plasmodium species place on one another. Investigations of malaria protection determinants and virulence factors that contribute to the complexity of the disease should advance our understanding of malaria pathogenesis.

INTRODUCTION

The global public health problem of malaria persists today, as drug resistance of Plasmodium malaria parasites and the limits of insecticides against mosquitoes undermine control measures that seemed so promising 50 yr ago. Bolstered by the initial successes of chloroquine as an antimalarial drug and DDT as an insecticide, the World Health Organization (WHO) had embarked on a campaign in 1955 to eradicate malaria (Jeffery, 1976). Early successes in some areas of the globe were dramatic, and by the early 1960s malaria was reduced to very low levels in certain countries (Wernsdorfer, 1980). Unfortunately, maintenance of eradication measures became more difficult in the face of practical constraints and commitment limits, and the campaign began to lose force (Henderson, 1999; Aylward et al., 2000). Anopheline mosquito populations adapted to survive the height of DDT-spraying programs (Litsios, 1996), and chloroquine-resistant strains of Plasmodium falciparum were spreading in South America and Southeast Asia before 1960 (Payne, 1987). Malaria soon reestablished itself with devastating impact in India and other countries where eradication had seemed nearly within grasp (Sharma, 1996).

Natural selection in response to chemical control measures is a recent example of evolution in the relationships between malaria parasites, mosquitoes, and humans. Other examples of selection and genome– shaping events have arisen in the long history of interactions between these species. These include a variety of human genetic polymorphisms that have been shown to protect against the disease.

Human malarias are caused by four different Plasmodium species. P. falciparum is in a deep evolutionary clade of its own and is responsible for the most acute and deadly form of malaria. P. vivax, P. malariae, and P. ovale fall among other Glades that include species with longstanding evolutionary relationships with numerous other primates, perhaps explaining the tendency of these parasites to produce less severe forms of disease. Here we review some central features of malaria and discuss genetic adaptations in the hostparasite relationship. Further reading may be found in three recent books that give comprehensive and up-to– date summaries of accumulated knowledge on malaria (Sherman, 1998; Coluzzi and Bradley, 1999; Wahlgren and Perlmann, 1999).

OVERVIEW OF PLASMODIUM INFECTIONS IN HUMANS

All human Plasmodium species have fundamental similarities in their transmission cycles but differ in the manifestations of the disease they cause. Bites from infected anopheline mosquitoes transfer parasites into the human bloodstream, where they quickly make their way to the liver and invade hepatocytes. The parasites emerge from the liver after 1-3 wk (P. vivax and P. ovale can also remain in the liver in latent form and produce relapses months or years later). After emerging from the hepatocytes, the parasites infect erythrocytes in the bloodstream and proliferate by cycling through rounds of erythrocyte invasion, multiplication, and host cell lysis. These cycles lead to exponential expansion of the parasite populations and the pathogenesis of malaria. Recurring fevers, paroxysms, rigors, and sweats occur as erythrocytes rupture and release new invasive parasites into the bloodstream. Different species can cause fevers at different intervals because the rounds of replication differ in cycle time. P. falciparum, P. vivax, and P. ovale reinvade erythrocytes every 48 hr, whereas P. malariae does so every 72 hr, giving rise to the historical terms of tertian and quartan malaria, respectively (fevers on days 1, 3, … vs. fevers on days 1, 4, . . . ).

A dangerous feature of P. falciparum-infected erythrocytes is their ability to adhere to the endothelial cells that line the microvasculature and thereby sequester within critical tissues. This phenomenon is thought to enable the parasites to avoid passage through the spleen, where they could be destroyed. In addition, sequestration may favor parasite growth and reproduction through effects of the microcapillary gas environment. Unfortunately, sequestration in such organs as the brain, lungs, and placenta can produce serious complications. Severe anemia, coma, pulmonary edema, and placental compromise in pregnancy are among the most dangerous developments. Rosetting of infected erythrocytes with surrounding uninfected red cells may also contribute to sequestration within microvessels and aggravate the pathogenic effects of infection (for an overview of the clinical features of malaria, see Marsh, 1999).

While P. falciparum is responsible for nearly all deaths directly attributable to malaria, all Plasmodium species can cause exhausting and recurring illnesses that have profound effects on individual productivity and fitness. Of these, the greatest burdens are produced by P. falciparum and P. vivax. Economic assessments have shown that a single bout of malaria results in a loss of 5-20 working days, and one study has shown that an agricultural family afflicted by malaria may be as much as 60% less productive than a family without malaria (Oaks et al., 1991). Depending on the characteristics of disease transmission and pathogenesis, some economic estimates may underrepresent the impact of malaria in communities where children are primary victims. Recent analyses have weighed the hidden costs of pain and suffering, increased susceptibility to other infectious diseases, and adverse demographic effects of the disease (http://www.malaria.org/ jdsachseconomic.html). When these standards are used to gauge the costs incurred by malaria, they show its enormous potential to act as a selective force.

While a single bite by an infected mosquito is sufficient to cause malaria, studies from Kenya have shown that only about half of such bites actually transmit the infection to children, and only small percentages of these children go on to develop severe complications from malaria (Marsh, 1992). Individuals who have had several episodes of malaria usually become less susceptible to the worst effects of the disease because of acquired clinical immunity (premunition), meaning that their immune systems have “learned” how to cope with the disease. Inherited traits may also contribute significant protection against severe complications of malaria. We now review what is known about many of these traits in the context of host-parasite evolution.

Thalassemias and hemoglobinopathies protect against the severe effects of malaria

Many human polymorphisms that protect against severe manifestations of malaria are erythrocyte related, reflecting the importance of this cell as the primary refuge of the parasite during infection and disease. Mutations responsible for hemoglobin underproduction (thalassemias) or hemoglobin variants (hemoglobinopathies) are well recognized in this regard.

Over 50 yr ago, J. B. S. Haldane hypothesized that thalassemia may offer a protective effect against malaria (Haldane, 1949). Since that time, thalassemias have been shown to result from a number of diverse mutations in either the ot- or beta-globin genes, causing a decrease or loss of globin production (Weatherall and Clegg, 1981). Several lines of evidence have supported the hypothesis that malaria is the selective force behind these mutations. First, the alpha- and beta-thalassemias have a distribution that overlaps with malaria endemicity, even though thalassemias are associated with hundreds of alleles that arose in different times and places (Flint et al., 1998). Second, epidemiologic studies have demonstrated associations between protection against malaria and certain thalassemias (Flint et al., 1986; Allen et al., 1997; Sakai et al., 2000). Some reports have suggested that the protective effect imparted by oa-thalassemia is due to modified antigen recognition on the surface of the parasitized erythrocyte (Luzzi et al., 1991). It has also been proposed that alpha– thalassemia may be associated with higher levels of P. vivax infection early in life and that this may heighten immunologic defenses and provide better protection from more dangerous, subsequent P. falciparum infections (Williams et al., 1996).

A few years after Haldane’s predictions, A. C. Allison advanced the hypothesis for malaria’s role in the selection of human polymorphisms when he proposed that individual heterozygotes for sickle-cell hemoglobin are protected against the disease (Allison, 1954). Abundant evidence subsequently reinforced the idea that individuals heterozygous for the sickle-cell allele (sickle-trait; HbAS) are protected against the severe effects of malaria (Hill et al., 1992; Aluoch, 1997). Although differences in the erythrocyte’s ability to support parasite growth in vitro have been advocated as a protective mechanism (Friedman, 1978, 1979; Pasvol et al., 1978), parasitemia data in normal and HbAS individuals have not been readily explained by these differences (Gendrel et al., 1991). Protection is more likely the result of an HbS effect that leads to an early and enhanced acquisition of protective immunity against malaria (Bayoumi, 1987; Bayoumi et al., 1990). The finding that the hemoglobin S (HbS) mutation has arisen on at least four different occasions in Africa and the Middle East (Wainscoat et al., 1983) is further support for the protective value of the HbS gene.

The homozygous sickle-cell condition (HbSS) is responsible for the deadly effects of sickle-cell anemia, whereas the heterozygous condition is usually asymptomatic. Selection for AS carriers by malaria and selection against SS individuals by sickle-cell anemia is thus an example of a balanced polymorphism whereby an allele that is detrimental in the homozygous state is maintained due to a survival advantage among heterozygotes.

Other predominant hemoglobin variants also have geographic distributions that suggest selection by malaria. HbE is the second most prevalent hemoglobin variant in the world. It is distributed throughout much of Southeast Asia and has gene frequencies greater than 0.10 in some regions (Ingram, 1986). Protection from malaria has been the conclusion of several studies (Nagel et al., 1981; Vernes et al., 1986; Kitayaporn et al., 1992; Hutagalung et al., 1999).

HbC is another common variant in West Africa, where it occurs in some populations at gene frequencies of 0.12 or more (Ingram, 1986). An interesting feature of HbC is that it contains an amino acid substitution at exactly the same beta-6 position as the HbS mutation. Reduced parasite growth in HbCC cells has been reported under in vitro conditions (Friedman et al., 1979; Olson and Nagel, 1986), but high parasitemias readily occur in vivo in P. falciparum-infected HbCC individuals (Agarwal et al., 2000). Recent epidemiologic data have provided evidence of a protective effect of heterozygous and homozygous HbC against malaria in certain populations of West Africa (Agarwal et al., 2000; Modiano et al., 2001). In these populations, the prevalence of HbS was found to be lower than that of HbC, in contrast to populations elsewhere in Africa where rates of HbC are lower and a protective effect of HbC trait could not be demonstrated (Molineaux and Gramiccia, 1980; Guinet et al., 1997). This evidence for different protective effects from HbC suggests the interesting possibility that population-specific factors, including differences in genetic background, may have a strong influence on the distributions of haemoglobin mutations in malarious regions.

Other polymorphisms that protect against malaria

A number of other polymorphic genes have also come to be seen as contributory to producing malaria resistance. Like the thalassemias and hemoglobinopathies, some of these mutations were first identified as medical conditions. As Geoffrey Pasvol points out, “To view many of these variants as ‘defects’.. . is naive. Many of these polymorphic variants have served the human genome well and must be considered in the context of providing a selective advantage in the face of dangerous life-threatening pathogens” (Pasvol, 1996).

At the plasma membrane, the P. vivax merozoite requires the Duffy chemokine receptor for erythrocyte invasion. A large percentage of the African population, as well as many American blacks, is Duffy negative; these individuals lack the receptor on their red blood cells and as a result are not infected by P. vivax (Miller et al., 1975, 1976). In these individuals, expression of the gene is blocked only in developing erythrocytes by a mutation of the promoter region that disrupts binding of the GATA 1 erythroid transcription factor (Tournamille et al., 1995).

Changes in the membrane of erythrocytes can also affect the outcome of infection. Some changes caused by mutations in the erythrocyte membrane anion exchanger (AE1 or Band 3) are examples. Changes in the coding region of Band 3 are known to produce a syndrome called Southeast Asian ovalocytosis (SAO). This syndrome is associated with malaria endemicity in parts of the western Pacific (Mgone et al., 1996). Ovalocytic erythrocytes are thought to have reduced susceptibility to parasite invasion (Castelino et al., 1981; Kidson et al., 1981; Hadley et al., 1983; Cattani et al., 1987). The mechanism of this inhibition is unclear, but it has been suggested that altered binding of SAO Band 3 to parts of the cytoskeleton could decrease cell deformability or limit the usual redistribution of the protein that is observed when the parasite tries to invade (Jarolim et al., 1991). Recent epidemiologic data also suggest a protective effect against cerebral malaria (Allen et al., 1999), which may point to an effect in another aspect of pathogenesis.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a syndrome that results in decreased activity of a metabolic pathway that protects the interior of the cell from oxidant stress. G6PD deficiency may be the most common human enzymopathy in the world, as it is present in nearly 400 million people. Like the patterns of other polymorphisms we have described, its distribution correlates with malaria endemicity in Africa, Asia, the Middle East, and the Mediterranean. Epidemiologic field data and in vitro studies support associations between malaria resistance and the enzyme deficiency (Ruwende et al., 1995; Ruwende and Hill, 1998). The mechanism by which it might protect against malaria is still unknown. Some evidence suggests that the accumulation of toxic oxidized substances in the cell can inhibit parasite multiplication (Golenser et al., 1988). Other studies suggest that infected cells may be more susceptible to phagocytosis or hemolysis as a result of increased cytolytic compounds and membrane damage (Janney et al., 1986; Cappadoro et al., 1998).

Immune system polymorphisms have been documented for malaria as for other infectious diseases. Epidemiologic data have suggested that the most common human leukocyte antigen type in West Africa (HLA-B53) is associated with resistance to severe malaria (Hill et al., 1991, 1992). This would be consistent with evolution of variation in the major histocompatibility complex (MHC) of the human immune system by infectious agents. Polymorphisms present within the promoter region of the tumor necrosis factor (TNF) cytokine have been implicated in cerebral malaria pathogenesis, but these are associated with the presence of, rather than protection from, severe cerebral manifestations (McGuire et al., 1994, 1999; Knight et al., 1999). Selection against these polymorphisms has been proposed to be counterbalanced by other biologic advantages, such as enhanced resistance against microbes, or the gene may be in linkage disequilibrium with another highly selected component of the MHC.

Evolution of Plasmodium species

Based on comparisons of genetic sequences from a number of parasite species, it is believed that the genus Plasmodium originated ~150 million years ago, possibly as early as the split between birds and reptiles (Escalante and Ayala, 1994). Today there is a variety of extant species that parasitize birds, reptiles, and rodents, as well as human and nonhuman primates. Species that parasitize humans are found in three deeply rooted branches; genetic data suggest the P. malariae and P. vivax branches diverged ~100 million years ago, and the branch that gave rise to P. falciparum split away even earlier (Escalante et al., 1995).

Comparisons of the available DNA sequences from several species were thought to suggest that P. falciparum may have come to humans by a recent lateral transfer from avian hosts (McCutchan et al., 1984; Waters et al., 1991, 1993). This hypothesis appeared to be consistent with the idea that relatively new pathogens are less well adapted to their host and correspondingly produce more malignant and dangerous disease. Additional data, however, have shown that P. falciparum is very closely related to a chimpanzee parasite, P. reichenowi, and that these two parasites share a common ancestor from 5-6 million years ago, about the time of the divergence of the human and the chimpanzee lineages (Escalante and Ayala, 1994; Escalante et al., 1995). Subsequent studies of sporozoite protein sequences have led to the conclusion that these two parasites share ancestral features with Plasmodium species that infect birds but, if transfer of a bird parasite to a primate occurred, such a transfer would have happened in an evolutionary distant progenitor to humans and chimpanzees (McCutchan et al., 1996).

Comparisons of genes from regional isolates have led to reports that P. falciparum emerged only recently through a population bottleneck in Africa (Rich et al., 1998; Rich and Ayala, 1998, 2000; Ayala et al., 1999; Conway et al., 2000). Some objections have been raised to these conclusions because of the need to interpret the relative paucity of synonymous mutations in P. falciparum genes (Hughes and Verra, 1998; Saul, 1999). Although low numbers of non-coding single nucleotide polymorphisms (SNPs) were reported to support an age of 3,200 to 7,700 years for the bottleneck from which all extant P. falciparum emerged (Volkman et al., 2001), an estimated age of 100,000 to 180,000 years was subsequently found for this bottleneck from an analysis of 62 synonymous and 31 non-coding SNPs (Mu et al., 2002).

Development of agriculture probably facilitated the spread of P. falciparum in Africa when human agricultural practices brought about changes in speciation and anthropophilic behavior of anopheline mosquito populations. This may have resulted in an increase in malaria transmission and perhaps selection of more aggressive strains of P. falciparum parasites (Coluzzi, 1999). Haplotype analysis indicates that the major G6PD enzyme deficiency, G6PD A^sup -^, arose as a malaria protective polymorphism between 3,000 and 11,000 years ago, in the timeframe of the spread of agriculture and animal domestication in the Middle East and Northeast Africa (Tishkoff et al., 2001). P. falciparum probably was not present in the Western Hemisphere until the colonization of the Americas by Europeans and the introduction of African slaves (Coatney et al., 1971).

Development of drug resistance in Plasmodium

The widespread use of synthetic antimalarials in the 20th century altered P. falciparum populations by selecting drug-resistant strains. The premiere example is the development and spread of chloroquine resistance into nearly all malarious regions-a dramatic example of selection pressure acting in our own time. Chloroquine resistance was first observed in the late 1950s at separate foci in South America and Southeast Asia (Payne, 1987). It has since been linked to mutations in the P. falciparum protein PfCRT, a molecule that likely functions as a transporter in the parasite’s digestive vacuole membrane (Fidock et al., 2000). Field studies and population surveys of PfCRT mutations have suggested that chloroquine resistance arose in four distinct geographic foci (Wellems and Plowe, 2001; Wootton et al., 2002). Chloroquine resistance in P. vivax was first reported in the late 1980s (Rieckmann et al., 1989). The three-decade interval between the appearance of resistance in P. falciparum and in P. vivax is thought to be consistent with genetic findings that there are different mechanisms of drug resistance in these two species (Nomura et al., 2001).

Plasmodium genome shaping by host-parasite interactions

In P. falciparum malaria, parasites evade immune destruction by altering the antigenic and adhesive properties of infected erythrocytes. This ability is attributed to a major variable erythrocyte membrane protein (PfEMP1) that parasites place on the erythrocyte surface (Baruch et al., 1995). In individual parasites, PfEMP1 is an exclusively expressed product from one of about 50 different var genes within the genome (Su et al., 1995; Chen et al., 1998; Scherf et al., 1998). Parasites occasionally and spontaneously switch expression from one var gene to another, producing different PfEMP1 molecules and altering the antigenic properties of the infected cells (Smith et al., 1995). During P. falciparum infections, such switching gives rise to antigenically diverse subpopulations that must be continually chased by the immune response (Newbold, 1999). In field populations, vast numbers of var gene repertoires are present among different parasites (Kyes et al., 1997). The capacity for generating new antigenic forms is comparable to that of another human parasite, the African trypanosome (Rudenko, 1999), and represents a critical survival strategy that has evolved under continuous pressure from host defenses (Freitas-Junior et al., 2000).

There is evidence for coevolutionary cycles of selection and adaptation in gene-for-gene struggles between the parasite and the host. The protective effect imparted by the HLA-1353 type may involve an immune response to the P. falciparum liver-stage antigen LSA-1 (Hill et al., 1992). Analyses of immune responses to parasite LSA-1 polymorphisms have led to the suggestion that the prevalence of parasite polymorphisms may be affected by HLA types in human populations (Gilbert et al., 1998; Plebanski et al., 1999). It has also been proposed that the prevalence of sickle-cell trait can influence the genetic structure of parasite populations. Distributions of the P. falciparum genes encoding the merozoite surface proteins Msp-1 and Msp-2 have been reported to be skewed with the occurrence of HbS trait in some regions (Ntoumi et al., 1997; Konate et al., 1999).

CONCLUSION

The ability of Plasmodium spp. and their mosquito and human hosts to adapt in response to selective pressure emphasizes the need for continued research to understand and control malaria. The catalog of human polymorphisms that reduce disease severity and the continual generation of new diversity in parasite populations testify both to the impact of malaria and its persistence as a major public heath burden. By exploring the protective determinants and virulence factors that arise from evolutionary pressures in malaria, we may come to better understand the disease and possibly identify new approaches to its control.

1 From the Symposium Living Together: The Dynamics of Symbiotic Interactions, presented at the Annual Meeting of the Society for Integrative and Comparative Biology, 3-7 January 2001, at Chicago, Illinois.

REFERENCES

Agarwal, A., A. Guindo, Y. Cissoko, J. G. Taylor, D. Coulibaly, A. Kone, K. Kayentao, A. Djimde, C. V. Plowe, O. Duombo, T. E. Wellems, and D. Diallo. 2000. Hemoglobin C associated with protection from severe malaria in the Dogon of Mali, a West African population with a low prevalence of hemoglobin S. Blood 96:2358-2363.

Allen, S. J., A. O’Donnell, N. D. E. Alexander, M. P. Alpers, T E. A. Peto, J. B. Clegg, and D. J. Weatherall. 1997. alpha^sup +^-Thallassemia protects children against disease due to malaria and other infections. Proc. Natl. Acad. Sci. U.S.A. 94:14736-14741.

Allen, S. J., A. O’Donnell, N. D. Alexander, C. S. Mgone, T E. A. Peto, J. B. Clegg, M. P Alpers, and D. J. Weatherall. 1999. Prevention of cerebral malaria in children in Papua New Guinea by Southeast Asian ovalocytosis band 3. Am. J. Trop. Med. Hyg. 60:1056-1060.

Allison, A. C. 1954. Polymorphism and natural selection in human populations. Cold Spring Harb. Symp. Quant. Biol. 29:137-149. Aluoch, J. R. 1997. Higher resistance to Plasmodium falciparum

infection in patients with homozygous sickle cell disease in western Kenya. Trop. Med. Int. Health. 2:568-571.

Ayala, E J., A. A. Escalante, and S. M. Rich. 1999. Evolution of Plasmodium and the recent origin of the world populations of Plasmodium falciparum. Parassitologia 41:55-68.

Aylward, B., K. A. Hennessey, N. Zagaria, J. Olive, and S. Cochi. 2000. When is disease eradicable? 100 years of lessons learned. Am. J. Public Health 90:1515-1520.

Baruch, D. I., B. L. Pasloske, H. B. Singh, X. Bi, X. C. Ma, M. Feldman, T E Taraschi, and R. J. Howard. 1995. Cloning the P. falciparum gene encoding PfEMP1, a malarial variant antigen and adherence receptor on the surface of parasitized human erythrocytes. Cell 82:77-87.

Bayoumi, R. A. 1987. The sickle-cell trait modifies the intensity and specificity of the immune response against P. falciparum ma

laria and leads to acquired protective immunity. Med. Hypotheses 22:287-298.

Bayoumi, R. A., Y. A. Abu-Zeid, N. H. Abdulhadi, B. 0. Saeed, T G. Theander, L. Hviid, H. W. Ghalib, A. H. Nugud, S. Jepsen, and J. B. Jensen. 1990. Cell-mediated immune responses to Plasmodium falciparum purified soluble antigens in sickle-cell trait subjects. Immunol. Lett. 25:243-249.

Cappadoro, M., G. Girabaldi, E. O’Brien, E Turrini, E Mannu, D. Ulliers, G. Simula, L. Luzzatto, and P Arese. 1998. Early phagocytosis of glucose-6-phosphate dehydrogenase (G6PD)deficient erythrocytes parasitized by Plasmodium falciparum may explain malaria protection in G6PD deficiency. Blood 92: 2527-2534.

Castelino, D., A. Saul, P. Myler, C. Kidson, H. Thomas, and R. Cooke. 1981. Ovalocytosis in Papua New Guinea-dominantly inherited resistance to malaria. S. E. Asian Trop. Med. Public Health 12:549-555.

Cattani, J. A., F D. Gibson, M. P. Alpers, and G. G. Crane. 1987. Hereditary ovalocytosis and reduced susceptibility to malaria in Papua New Guinea. Trans. R. Soc. Trop. Med. Hyg. 81:705709.

Chen, Q., V. Fernandez, A. Sundstrom, M. Schlichtherle, S. Datta, P Hagblom, and M. Wahlgren. 1998. Developmental selection of var gene expression in Plasmodium falciparum. Nature 394: 392-395.

Coatney, G. R., W. E. Collins, M. Warren, and P G. Contacos. 1971. The primate malarias. U.S. Dept. Health, Bethesda.

Coluzzi, M. and D. Bradley. (eds.) 1999. The malaria challenge after one hundred years of malariology. (vol. 41, nos. 1-3. Parassitologia) Lombardo Editore, Rome.

Coluzzi, M, 1999. The clay feet of the malaria giant and its African roots: Hypotheses and inferences about origin, spread, and control of Plasmodium falciparum. Parassitologia 41:277-285.

Conway, D. J., C. Fanello, J. M. Lloyd, B. M. Al-Joubori, A. H. Baloch, S. D. Somanath, C. Roper, A. M. J. Odoula, B. Mulder, M. M. Povoa, B. Singh, and A. W. Thomas. 2000. Origin of Plasmodium falciparum malaria is traced by mitochondrial DNA. Mol. Biochem. Parasitol. 111:163-171.

Escalante, A. A. and F J. Ayala. 1994. Phylogeny of the malarial genus Plasmodium, derived from rRNA gene sequences. Proc. Natl. Acad. Sci. U.S.A. 91:11373-11377.

Escalante, A. A., E. Barrio, and F J. Ayala. 1995. Evolutionary origin of the human and primate malarias: Evidence from the circumsporozoite protein gene. Mol. Biol. Evol. 12:616-626.

Fidock, D. A., T Nomura, A. K. Talley, R. A. Cooper, S. M. Dzekunov, M. T Ferdig, L. M. B. Ursos, A. B.-S. Sidhu, B. Naude, K. W. Deitsch, X-z. Su, J. C. Wootton, P D. Roepe, and T E. Wellems. 2000. Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol. Cell 6:861-871.

Flint, J., A. V. S. Hill, D. K. Bowden, S. J. Oppenheimer, P. R. Sill, S. W. Serjeantson, J. Bana-Koiri, K. Bhatia, M. P Alpers, A. J. Boyce, D. J. Weatherall, and J. B. Clegg. 1986. High frequencies of ot-thalassemia are the result of natural selection by malaria. Nature 321:744-749.

Flint, J., R. M. Harding, A. J. Boyce, and J. B. Clegg. 1998. The population genetics of the hemoglobinopathies. Bailliere’s Clin. Haematol. 11:1-51.

Freitas-Junior, L. H., E. Bottius, L. A. Pirrit, K. W. Deitsch, C. Scheidig, F Guinet, U. Nehrbass, T E. Wellems, and A. Scherf. 2000. Frequent ectopic recombination of virulence factor genes in telomeric chromosome clusters of P. falciparum. Nature 407: 1018-1022.

Friedman, M. J. 1978. Erythrocytic mechanism of sickle cell resistance to malaria. Proc. Natl. Acad. Sci. U.S.A. 75:1994-1997. Friedman, M. J. 1979. Ultrastructural damage to the malaria parasite in the sickled cell. J. Protozool. 26:195-199.

Friedman, M. J., E. E Roth, R. L. Nagel, and W. Trager. 1979. The role of hemoglobins C, S and NB^LT in the inhibition of malaria parasite development in vitro. Am. J. Trop. Med. Hyg. 28:777780.

Gendrel, D., M. Kombila, M. Nardou, C. Gendrel, E Djouba, and D. Richard-Lenoble. 1991. Protection against Plasmodium fal

ciparum infection in children with hemoglobin S. Ped. Infect. Dis. J. 10:620-621.

Gilbert, S. C., M. Plebanski, S. Gupta, J. Morris, M. Cox, M. Aidoo, D. Kwiatkowski, B. M. Greenwood, H. C. Whittle, and A. V. S. Hill. 1998. Association of malaria parasite population structure, HLA, and immunological antagonism. Science 270:11731176.

Golenser, J., J. Miller, D. T, Spira, N. S. Kowoser, J. A. Vande Waa, and J. B. Jensen. 1988. Inhibition of intraerythrocytic development of Plasmodium falciparum in glucose-6-phosphate dehydrogenase deficient erythrocytes is enhanced by oxidants and crisis form factor. Trop. Med. Parasitol. 39:272-276.

Guinet, E, D. A. Diallo, D. Minta, A. Dicko, M. S. Sissoko, M. M. Keita, T. E. Wellems, and 0. Doumbo. 1997. A comparison of the incidence of severe malaria in Malian children with normal and C-trait hemoglobin profiles. Acta Tropica 68:175-182.

Hadley, T, A. Saul, G. Lamony, D. E. Hudson, L. H. Miller, and C. Kidson. 1983. Resistance of Melanesian elliptocytes (ovalocytes) to invasion by Plasmodium knowlesi and Plasmodium falciparum malaria parasites in vitro. J. Clin. Invest. 71:780782.

Haldane, J. B. S. 1949. The rate of mutation of human genes. Proc. VIII Int. Cong. Genet. Hereditas. 35(suppl):267-273. Henderson, D. A. 1999. Eradication: Lessons from the past. Morb.

Mortal. Wkly. Rep. 48(suppl):16-22.

Hill, A. V. S., C. E. M. Allsopp, D. Kwaitkowski, N. M. Anstey, P Twumasi, P A. Rowe, S. Bennet, D. Brewster, A. J. McMichael, and B. M. Greenwood. 1991. Common West African HLA antigens are associated with protection against malaria. Nature 352:595-600.

Hill, A. V. S., J. Elvin, A. C. Willis, M. Aidoo, C. M. Allsopp, E M. Gotch, X. M. Gao, M. Takiguchi, B. M. Greenwood, A. R. M. Townsend, A. J. McMichael, and H. C. Whittle. 1992. Molecular analysis of the association of HLA-1353 and resistance to severe malaria. Nature 360:434-439.

Hughes, A. L. and E Verra. 1998. Ancient polymorphism and the hypothesis of a recent bottleneck in the malaria parasite Plasmodium falciparum. Genetics 150:511-513.

Hutagalung, R., P Wilairatana, S. Looareesuwan, G. M. Brittenham, M. Aikawa, and V. R. Gordeuk. 1999. Influence of hemoglobin E trait on the severity of falciparum malaria. J. Infect. Dis. 179: 283-286.

Ingram, V. 1986. Human hemoglobin varients. In H. F Bunn and B. G. Forget (eds.), Hemoglobin: Molecular, genetic, and clinical aspects, pp. 381-452. W. B. Saunders Co., Philadelphia.

Janney, S. K., J. H. Joist, and C. D. Fitch. 1986. Excess release of ferriheme in G6PD-deficient erythrocytes: Possible cause of haemolysis and resistance to malaria. Blood 67:331-333.

Jarolim, P, J. Palek, D. Amato, K. Hassan, P. Sapak, G. T. Nurse, H. L. Rubin, S. Zhai, K. E. Sahr, and S. Liu. 1991. Deletion in erythrocyte band 3 gene in malaria-resistant Southeast Asian ovalocytosis. Proc. Natl. Acad. Sci. U.S.A. 88:11022-11026.

Jeffery, G. M. 1976. Malaria control in the twentieth century. Am. J. Trop. Med. Hyg. 25:361-371.

Kidson, C., G. Lamont, A. Saul, and G. T Nurse. 1981. Ovalocytic erythrocytes from Melanesians are resistant to invasion by malaria parasites in culture. Proc. Natl. Acad. Sci. U.S.A. 78:58295832.

Kitayaporn, D., K. E. Nelson, P. Charoenlarp, and T. Pholpothi. 1992. Haemoglobin-E in the presence of oxidative substances from fava bean may be protective against Plasmodium falciparum malaria. Trans. R. Soc. Trop. Med. Hyg. 86:240-244.

Knight, J. C., I. Udalova, A. V. S. Hill, B. M. Greenwood, N. Pershu, K. Marsh, and D. Kwiatkowski. 1999. A polymorphism that affects OCT-1 binding to the TNF region is associated with severe malaria. Nat. Genet. 22:145-150.

Konate, L., J. Zwetyenga, C. Rogier, E. Bischoff, D. Fontenille, A. Tall, A. Spiegel, J.-F Trape, and 0. Merceraeu-Puijalon. 1999. The epidemiology of multiple Plasmodium falciparum infections. 5. Variation of Plasmodium falciparum msp-I and msp-2 allele prevalence and of infection complexity in two neighboring Senegalese villages with different transmission conditions. Trans. R. Soc. Trop. Med. Hyg. 93(suppl):SI/21-SI/28.

Kyes, S., H. Taylor, A. Craig, K. Marsh, and C. Newbold. 1997. Genomic representation of var gene sequences in Plasmodium falciparum field isolates from different geographic regions. Mol. Biochem. Parasitol. 87:235-238.

Litsios, S. 1996. The tomorrow of malaria. Pacific Press, Wellington, New Zealand.

Luzzi, G. A., A. H. Merry, C. I. Newbold, K. Marsh, G. Pasvol, and D. J. Weatherall. 1991. Surface antigen expression on Plasmadium falciparum-infected erythrocytes is modified in a- and thalassemia. J. Exp. Med. 173:785-791.

Marsh, K. 1992. Malaria-a neglected disease. Parasitology 104: S53-S69.

Marsh, K. 1999. Clinical features of malaria. In M. Wahlgren and P. Perlmann (eds.), Malaria: Molecular and clinical aspects, pp. 87-117. Harwood Academic Publishers, Amsterdam.

McCutchan, T E, J. B. Dame, L. H. Miller, and J. Barnwell. 1984. Evolutionary relatedness of Plasmodium species as determined by the structure of DNA. Science 225:808-811.

McCutchan, T F, J. C. Kissinger, M. G. Touray, M. J. Rogers, J. Li, M. Sullivan, E. M. Braga, A. U. Krettli, and L. H. Miller. 1996. Comparison of circumsporozoite proteins from avian and mammalian malarias: Biological and phylogenetic implications. Proc. Natl. Acad. Sci. U.S.A. 93:11889-11894.

McGuire, W., A. V. S. Hill, C. E. M. Allsopp, B. M. Greenwood, and D. Kwiatkowski. 1994. Variation in the TNF-a promoter region associated with susceptibility to cerebral malaria. Nature 371:508-511.

McGuire, W., J. C. Knight, A. V. S. Hill, C. E. M. Allsopp, B. M. Greenwood, and D. Kwiatkowski. 1999. Severe malarial anemia and cerebral malaria are associated with different tumor necrosis factor promoter alleles. J. Infect. Dis. 179:287-290.

Miller, L. H., S. J. Mason, J. A. Dvorak, M. H. McGinnis, and I. K. Rothman. 1975. Erythrocyte receptors for (Plasmodium knowlesi) malaria: Duffy blood group determinants. Science 189: 561-563.

Miller, L. H., S. J. Mason, D. F Clyde, and M. H. McGinnis. 1976. The Duffy-blood-group genotype, FyFy. N. Engl. J. Med. 295: 302-304.

Mgone, C. S., G. Koki, M. M. Panin, J. Kono, K. K. Bhatia, B. Genton, N. D. Alexander, and M. P Alpers. 1996. Occurrence of the erythrocyte band 3 (AEI) gene deletion in relation to malaria endemicity in Papua New Guinea. Trans. R. Soc. Trop. Med. Hyg. 90:228-231.

Modiano, D., G. Luoni, B. S. Sirima, J. Simpore, F Verra, A. Konate, E. Rastrelli, A. Oliviera, C. Calissano, G. M. Paganotti, L. D’Urbano, I. Sanou, A. Sawadogo, G. Modiano, and M. Coluzzi. 2001. Haemoglobin C protects against clinical Plasmodium falciparum malaria. Nature 414:305-308.

Molineaux, L. and G. Gramiccia. 1980. The Garki Project. Research on the epidemiology and control of malaria in the Sudan savanna of West Africa. World Health Organization, Geneva.

Mu, J., J. Duan, K. Makova, D. A. Joy, C. Q. Huynh, 0. H. Branch, W. Li, and X. Su. 2002. Chromosome-wide SNPs reveal an ancient origin for Plasmodium falciparum. Nature. (In press)

Nagel, R. L., C. Raventos-Suarez, M. E. Fabry, H. Tanowitz, D. Sicard, and D. Labie. 1981. Impairment of the growth of Plasmodium falciparum in HbEE erythrocytes. J. Clin. Invest. 68: 303-305.

Newbold, C. 1. 1999. Antigenic variation in Plasmodium falciparum: Mechanisms and consequences. Curr. Opin. Microbiol. 2:420425.

Nomura, T, J. M.-R. Carlton, J. K. Baird, H. A. del Portillo, D. J. Fryauff, D. Rathore, D. A. Fidock, X. Su, W. E. Collins, T F McCutchan, J. C. Wooton, and T E. Wellems. 2001. Evidence for different mechanisms of chloroquine resistance in two Plasmodium species that cause human malaria. J. Infect. Dis. 183: 1653-1661.

Ntoumi, F, C. Rogier, A. Dieye, J. F Trope, P. Millet, and 0. Mercereau-Puijalon. 1997. Imbalanced distribution of Plasmodium falciparum MSP-I genotypes related to sickle cell anemia. Mol. Med. 3:581-592.

Oaks, S. C., V. S. Mitchell, G. W. Pearson, and C. C. J. Carpenter.

(eds.) 1991. Malaria: Obstacles and opportunities. National Academy Press, Washington, D.C.

Olson, J. A. and R. L. Nagel. 1986. Synchronized cultures of P. falciparum in abnormal red cells: The mechanism of the inhibition of growth in HbCC cells. Blood 67:997-1001.

Pasvol, G. 1996. Malaria and resistance genes-they work in wondrous ways. Lancet 348:1532-1534.

Pasvol, G., D. J. Weatherall, and R. J. M. Wilson. 1978. Cellular mechanism for the protective effect of haemoglobin S against P. falciparum malaria. Nature 274:701-703.

Payne, D. 1987. Spread of chloroquine resistance in Plasmodium falciparum. Parasitol. Today 3:241-246.

Plebanski, M., E. A. M. Lee, C. M. Hannan, K. L. Flanagan, S. C. Gilbert, M. B. Gravenor, and A. V. S. Hill. 1999. Altered peptide ligands narrow the repertoire of cellular immune responses by interfering with T-cell priming. Nat. Med. 5:565-571.

Rich, S. M. and E J. Ayala. 1998. The recent origin of allelic variation in antigenic determinants of Plasmodium falciparum. Genetics 150:515-517.

Rich, S. M. and F J. Ayala. 2000. Population structure and recent evolution of Plasmodium falciparum. Proc. Natl. Acad. Sci. U.S.A. 97:6994-7001.

Rich, S. M., M. C. Licht, R. H. Hudson, and F J. Ayala. 1998. Malaria’s Eve: Evidence of a recent population bottleneck throughout the world populations of Plasmodium falciparum. Proc. Natl. Acad. Sci. U.S.A. 95:4425-4430.

Rieckmann, K. H., D. R. Davis, and D. C. Hutton. 1989. Plasmodium vivax resistant to chloroquine? Lancet 2:1183-1184. Rudenko, G. 1999. Genes involved in phenotypic and antigenic var

iation in African trypanosomes and malaria. Curr. Opin. Microbiol. 2:651-656.

Ruwende, C. and A. Hill. 1998. Glucose-6-phosphate dehydrogenase deficiency and malaria. J. Mol. Med. 76:581-588.

Ruwende, C., S. C. Khoo, R. W. Snow, S. N. R. Yates, D. Kwiatkowski, S. Gupta, P Warn, C. E. M. Allsopp, S. C. Gilbert, N. Peschu, C. I. Newbold, B. M. Greenwood, K. Marsh, and A. V. S. Hill. 1995. Natural selection of hemi- and heterozygotes for G6PD deficiency in Africa by resistance to malaria. Nature 376: 246-249.

Sakai, Y., S. Kobayashi, H. Shibata, H. Furuumi, T Endo, S. Fucharoen, S. Hamann, G. P. Acharya, T Kawasaki, and Y. Fukumaki. 2000. Molecular analysis of a-thalassemia in Nepal: Correlation with malaria endemicity. J. Hum. Genet. 45:127132.

Saul, A. 1999. Circumsporozoite polymorphisms, silent mutations and the evolution of Plasmodium falciparum. Parasitol. Today 15:38-39.

Scherf, A., R. Hernandez-Viras, P Buffet, E. Bottius, C. Benatar, B. Pouvelle, J. Gysin, and M. Lanzer. 1998. Antigenic variation in malaria: in situ switching, relaxed and mutually exclusive transcription of var genes during intra-erythrocytic development in Plasmodium falciparum. EMBO J. 17:5418-5426.

Sharma, V. P 1996. Re-emergence of malaria in India. Indian J. Med. Res. 103:26-45.

Sherman, I. W. (ed.) 1998. Malaria: Parasite biology, pathogenesis, and protection. ASM Press, Washington, D.C.

Smith, J. D., C. E. Chitnis, A. G. Craig, D. J. Roberts, D. E. Hudson

Taylor, D. S. Peterson, R. Pinches, C. I. Newbold, and L. H. Miller. 1995. Switches in expression of Plasmodium falciparum var genes correlate with changes in antigenic and cytoadherent phenotypes of infected erythrocytes. Cell 82:101-110.

Su, X., V. M. Heatwole, S. P Wertheimer, F Guinet, J. A. Herrfeldt, D. S. Peterson, J. A. Ravetch, and T. E. Wellems. 1995. The large and diverse gene family var encodes proteins involved in cytoadherence and antigenic variation of Plasmodium falciparum-infected erythrocytes. Cell 82:89-100.

Tishkoff, S. A., R. Varkonyi, N. Cahinhinan, S. Abbes, G. Argyropoulos, G. Destro-Bisol, A. Drousiotou, B. Dangerfield, G. Lefranc, J. Loiselet, A. Piro, M. Stoneking, A. Tagarelli, G. Tagarelli, E. H. Touma, S. M. Williams, and A. G. Clark. 2001. Haplotype diversity and linked disequilibrium at human G6PD: Recent origin of alleles that confer malarial resistance. Science 293:455-462.

Tournamille, C., Y. Colin, J. P. Cartron, and C. Le Van Kim. 1995. Disruption of a GATA motif in the Duffy gene promoter abolishes erythroid gene expression in Duffy-negative individuals. Nat. Genet. 10:224-228.

Vernes, A. J., J. D. Haynes, D. B. Tang, E. Dutoit, and C. L. Diggs. 1986. Decreased growth of Plasmodium falciparum in red cells containing haemoglobin E, a role for oxidative stress, and a sero-epidemiological correlation. Trans. R. Soc. Trop. Med. Hyg. 80:642-648.

Volkman, S. K., A. E. Barry, E. J. Lyons, K. M. Nielsen, S. M. Thomas, M. Choi, S. S. Thakore, K. P. Day, D. E Wirth, and D. L. Hard. 2001. Recent origin of Plasmodium falciparum from a single progenitor. Science 293:482-484.

Wahlgren, M. and P. Perlmann. (eds.) 1999. Malaria: Molecular and clinical aspects. Harwood Academic Publishers, Amsterdam.

Wainscoat, J. S., J. I. Bell, S. L. Them, D. R. Higgs, G. R. Sarjeant, T E. Peto, and D. J. Weatherall. 1983. Multiple origins of the sickle mutation: Evidence from beta S globin gene cluster polymorphisms. Mol. Biol. Med. 1:191-197.

Waters, A. P, D. G. Higgins, and T. F McCutchan. 1991. Plasmadiem falciparum appear to have arisen as a result of lateral transfer between avian and human hosts. Proc. Natl. Acad. Sci. U.S.A. 88:3140-3144.

Waters, A. P, D. G. Higgins, and T F McCutchan. 1993. Evolutionary relatedness of some primate models of Plasmodium. Mol. Biol. Evol. 10:914-923.

Weatherall, D. J. and J. B. Clegg. 1981. The thalassemia syndromes. Blackwell Scientific Publications, Oxford.

Wellems, T E. and C. V. Plowe. 2001. Chloroquine-resistant malaria. J. Infect. Dis. 184:770-776.

Wernsdorfer, W. H. 1980. The importance of malaria in the world. In J. P Kreier (ed.), Malaria: Epidemiology, chemotherapy, morphology, and metabolism, pp. 1-79. Academic Press, New York.

Williams, T N., K. Maitlan, S. Bennet, M. Ganczakowski, T E. A. Peto, C. I. Newbold, D. K. Bowden, D. J. Weatherall, and J. B. Clegg. 1996. High incidence of malaria in ot-thalassaemic children. Nature 383:522-525.

Wooten, J. C., X. Feng, M. T Ferdig, R. A. Cooper, J. Mu, D. I. Baruch, A. J. Magill, and X. Su. 2002. Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum. Nature. (In press)

ANDREW G. EVANS AND THOMAS E. WELLEMS2

Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892

2 E-mail: tew@helix.nih.gov

Copyright Society for Integrative and Comparative Biology Apr 2002

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