The co-evolution of people, plants, and parasites: biological and cultural adaptations to malaria*

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Malaria epidemiology and anti-malarial drugs Furthermore, agriculture was assisted by forest clearing and Today, malaria is virulently resurgent, with increased related environmental modifications that both encouraged severity and epidemicity. The number of malaria deaths and mosquito breeding and destroyed the habitats of non-human geographic distribution are more extensive than three primates who formerly served as the anopheline feeding decades ago. More than half the world’s population lives in targets and plasmodium hosts. The increasingly transformed malaria-endemic areas, where each year an estimated two environments of the modern era continue to support malaria billion are exposed, 500 million cases occur and infection at a very high rate of transmissibility.
results in more than two million deaths (Hoffman et al.
2002; Warhurst, 2002). What was heralded as the ‘imminent Malaria life cycle and transmission arrival’ of a malaria vaccine 20 years ago still has not mate-rialized (Rabinovich, 2002). Existing anti-malarial drugs are The complex plasmodial life cycle begins with gametocytes less effective, and insecticide resistance among anopheline that are ingested as part of the female mosquito’s blood vectors is a growing problem. Consequently, the options are meal, and that initiate sexual reproduction in the mosquito’s fewer, and more expensive. Once optimistic, the WHO has stomach. The motile zygote (ookinete) migrates through and in the last 10 years downgraded its objectives and shifted its encysts to the outer surface of the stomach wall (as an rhetoric from ‘eradication’ to ‘control’ (Najera, 2001).
oocyst). Asexual division (sporogony) within this oocystproduces large numbers of sporozoites, which migrate to thesalivary glands, and from there are injected into a vertebrate Natural products and malaria therapy
host when the mosquito takes another blood meal.
The urgency generated by plasmodial resistance to a In the vertebrate host asexual reproduction (schizogony) growing number of pharmaceutical agents has accelerated occurs first in the liver, the asymptomatic phase, and later in malaria drug research over the last two decades, with a circulating erythrocytes. Each sporozoite invades a single substantial amount of that effort devoted to natural hepatic cell and produces thousands of merozoites that products. A MEDLINE search for articles published during burst out of the liver cell and invade erythrocytes. The just the last 5 years located several hundred dealing intra-erythrocytic trophozoite (the ‘ring’ stage) reproduces specifically with anti-plasmodial plants. (Research on to form a multinucleated schizont, which contains a species- insecticides based on natural products, an important determined number of merozoites. When the schizont corollary to this work, is not addressed in the present paper.) matures, the erythrocyte ruptures and releases merozoites These publications range across studies of single species, that infect new erythrocytes. Completing the cycle, groups of plants from indigenous pharmacopoeias, isolated the sexual gametocytes that develop from some of the constituents, reversal of drug-resistance and influence on trophozoites are infective to the mosquito.
anti-malarial pharmaceutical agents. These articlespublished in the last 12 months are representative: single species: crude extracts of Uvaria klaineana The characteristic periodic fevers that are the signature of Engler and Diel (Annonaceae) are active against malaria are precipitated by synchronous parasite devel- chloroquine-resistant P. falciparum (Akendengue et al.
opment and erythrocyte rupture, which releases new 2002); extracts of Solanum nudum Dunal (Solanaceae) merozoites, malaria antigens and toxic metabolites. P. vivax have anti-falciparum activity (Pabon et al. 2002); and P. ovale are relatively benign infections that present indigenous anti-pyretics: thirteen species from the with 48 h (tertian) periodicity. P. malariae, also benign, has islands of São Tomé and Príncipe (Gulf of Guinea, a 72 h (quartan) periodicity. P. falciparum, malignant tertian off the west coast of Africa) show strong in vitro anti- malaria, evinces the most severe symptoms and highest falciparum activity, including against both hepatic and mortality, and is the principal target of anti-malarial drug erythrocyte forms, and several species are effective research. (Quotidian malaria with 24 h periodicity is usually in vivo against murine P. berghei (do Ceu de Madureira a double tertian infection by two distinct groups of P. vivax et al. 2002); various combinations of these Mali or two generations of P. falciparum, or a mixed P. vivax and plant substances act synergistically against malaria: P. falciparum infection.) Early signs of malaria are fever Mitragyna inermis (Willd.) O. Kuntze (Rubiaceae), and chills accompanied by tachycardia (rapid bounding Nauclea latifolia (Sm.) (Rubiaceae), Guiera pulse), nausea, vomiting, frequent urination and ‘flu-like’ senegalensis (Gmel.) (Combretaceae) and Feretia symptoms. Interfebrile episodes are characterized by leuco- apodanthera (Del.) (Rubiaceae; Azas et al. 2002); paenia and thrombocytopaenia (abnormally low numbers constituents: the alkaloids febrifugine-1 and of leucocytes and platelets). Later developments include isofebrifugine-2 from the root of Dichroa febrifuga haemolytic anaemia and kidney and other organ Lour. have strong activity against P. falciparum dysfunction, including hepatosplenomegaly and jaundice. In (Kikuchi et al. 2002); dioncophylline E, the novel the terminal stages, P. falciparum becomes ‘cerebral naphthylisoquinoline alkaloid from Dioncophyllum malaria’ and ‘blackwater fever’ (haemoglobinuria). Where thollonii (Dioncophyllaceae), is active against malaria is endemic, children younger than 5 years bear the chloroquine-sensitive and -resistant P. falciparum burden of morbidity and mortality, while older children and adults may develop an ‘immunity tolerance’, a protection reversal of drug-resistance: the monoindole alkaloids iso- against super-infection (Taylor-Robinson, 2002).
retuline and icajine from Strychnos spp. (Loganiaceae) reverse chloroquine resistance (Frederich et al. 2001); positive mode. Redox refers to linked reduction and artemisinin from Artemisia annua L. (Asteraceae) oxidation reactions in which reducing agents are H donors reverses chloroquine resistance (Pradines et al. 2001); influence on anti-malarial pharmaceutical agents: the The importance of oxidation for malaria is that erythro- monoindole alkaloid icajine from Strychnos spp. acts cytes depend on suppression of chemical equilibrium with synergistically with mefloquine (Frederich et al. 2001); O2 at the same time that O2 transport is their principal artemisinin from A. annua acts synergistically both with function. Increased, and not compensated, oxidation even- anti-malarial pharmaceutical agents (e.g. mefloquine) tuates in cell damage, which releases immature parasite and with other plant-derived anti-malarial substances forms that cannot transfer the infection to new erythrocytes.
(e.g. quinine from Cinchona spp. (Rubiaceae); Gupta Intra-erythrocytic oxidation may increase as a consequence et al. 2002; Nosten & Brasseur, 2002).
of ordinary metabolic fluctuations, genetic anomalies andsome foods and drugs. Oxidation also is increased by certain Although many of these studies are based on plants pathologies, including plasmodial infection. This situation is identified in indigenous pharmacopoeias, they provide only apparent in malaria-infected erythrocytes that contain up to minimal ethnographic depth. Typically, the findings are five times the normal concentration of methaemoglobin, an presented as decontextualized catalogues of plants and lists oxidized form of haemoglobin. Additional evidence for of phytoconstituents. This information provides valuable oxidation during malaria infection includes elevated levels baseline data, but disappoints from the standpoints of both of the coenzymes NAD and NADP, and glutathione practice and theory. Few of these studies offer insights into (oxidized form) relative to their reduced counterparts the experience of real people in specific cultural and (NADH, reduced glutathione). Other signs of oxidation are eco-political settings; and none projects the findings against lipid peroxidation, spontaneous generation of oxygen radical species and parasite appropriation of host To fill some of those gaps, the present paper draws superoxide dismutase. These indicators reflect intra- attention to the larger context in which plant use occurs.
erythrocytic oxidation of parasite origin and erythrocyte Specifically, emphasis is given to how the use of plants in response, as well as activation of leucocyte defence (Etkin, more than one application (principally as medicines and 1997; Scott & Eaton, 1997; Schwartz et al. 1999; Kemp foods), and in particular ways (in combinations, in particular doses and sequences), can affect human health. Further, The oxidant action of artemisinin accelerates oxidative consideration is given to how the selection of medicinal erythrocyte senescence and premature destruction, and plants has evolved over millennia as part of the larger release of immature parasites. Oxidation also affects the human effort to mediate illness. The objective is to present parasite directly through damage to membranes surrounding co-evolution as a theoretical link to illuminate how medical the nucleus, food vacuole, mitochondria and endoplasmic cultures manage the relationships among humans, plants, reticulum (Dhingra et al. 2000). The oxidizing effect of herbivores and their respective pathogens. A theory-driven artemisinin finds analogues in pharmaceutical anti-malarial integrated research programme should take the place of agents (e.g. primaquine, dapsone, divicine, alloxan, mena- ‘hit-and-miss’ strategies for identifying new drugs. This dione) whose action is mediated by activated oxygen issue is approached by introducing the anti-malarial plant Artemisia annua, in many ways a quintessential indigenous 2O2, hydroxyl and superoxide radicals, and medicine: its history as a Chinese fever medicine isthousands of years old; its active principle and itsderivatives produce the most rapid parasitological and clinical responses; it has the broadest stage specificity; it is The mode of action of several other plants with demon- non-toxic and active by all routes of administration; it strated anti-malarial activity is also attributed to constituents potentiates pharmaceutical agents such as chloroquine and that promote erythrocyte oxidation. This partial list mefloquine; it is effective against multi-drug-resistant illustrates the botanical and ecological diversity of species strains of malaria (Li & Wu, 1998; Balint, 2001; Christen & that share this particular biochemical profile (Etkin, 1997): Veuthey, 2001; Gupta et al. 2002).
Cyperus rotundus L. (Cyperaceae), mixed auto-oxidationproducts of β-selinene; Chenopodium ambrosioides L.
The chemical basis of anti-malarial action
(Chenopodiaceae), ascaridole which is an endoperoxide;Gossypium spp. (Malvaceae), gossypol; Bidens pilosa L. (Asteraceae), phenyl-hepatrine; Hypericum japonicum My specific interest in A. annua lies in what has been called its unique mode of action, oxidation (for example, see Price, Research on northern Nigerian anti-malarial plant 2000). It will be argued that oxidation is not a novel medicines and food species suggests that the efficacy of bioactivity, and that mode of action will be put forward as those plants in the prevention and treatment of malaria is the framework for the theoretical co-evolutionary model.
attributed at least in part to oxidant action. Extracts of The active constituent in this plant is artemisinin, a these species are particularly compelling (Etkin & Ross, compound distinguished by a dioxygen (endoperoxide) 1997): Acacia nilotica Del. (Fabaceae); Azadirachta indica bridge that connects two parts of the C skeleton. Biochem- A. Juss (Meliaceae); Cassia occidentalis L. (Fabaceae); ically, then, artemisinin is an ‘oxidant’. It kills plasmodia by C. tora L. (Fabaceae); Guiera senegalensis JF Gmel shifting the intracellular redox balance to a more electro- Oxidants have been identified and chemically charac- Comprehensive co-evolutionary perspectives
terized in other plants, e.g. Allium cepa L. (Liliaceae), Discussion up to this point has established that plants Cinnamomum verum J. Presl. (Lauraceae), Myristica offer substantial promise for the development of new fragrans Houtt. (Myristicaceae), Ocimum basilicum anti-malarial substances, and that oxidation provides a (Lamiaceae), Syzygium aromaticum Merr. & Perry cogent unifying principle for identifying candidate new (Myrtaceae). Although anti-malarial activity has not been drugs. Oxidation also provides focus for understanding reported for these species, they all play a prominent role in how other uses of the same plants expand exposure to the medicines and cuisines of diverse human cultures.
biodynamic activities. Food plants are especially important No doubt other oxidant plant substances can be identified as they tend to be consumed in larger volume and regularly.
as well, and all fit the comprehensive model developed Other plant uses (cosmetics, hygiene, dyes and craft manu- herein for oxidant anti-malarial substances.
facture) also afford contact with constituents that havepharmaco-dynamic potential.
From a human-centered, or even animal-centered, perspective, it might seem paradoxical that plants generate Populations are exposed to plant substances not only in oxidants. After all, oxidants are detrimental to most life medicine, but also in other contexts, most prominently in the forms. It might also seem curious that taxonomically- diet. There is great potential for both synergy and diverse plants share this chemical signature. However, in a antagonism in the interactions among drugs and foods.
broad co-evolutionary model we can understand the Vitamins A and E, which occur widely in nature, are production of these metabolites as protective; e.g. some powerful antioxidants. In that way they antagonize oxidant oxidants act as toxins and anti-feeding agents to discourage anti-malarial drugs and contribute to higher parasite counts insects and herbivores, others are anti-microbial and protect in malaria infection. Conversely, deficiencies of vitamins A against plant pathogens and other oxidant compounds are and E protect against fulminant infection. Riboflavin and Se allelo-chemicals that suppress the growth of competing deficiencies also contribute to oxidation and suppress plants (Howe & Westley, 1988; Harborne, 1993). In these human and animal malarias. As transition metals, Fe and Cu ways the anti-malarial action of oxidant plants is an artifact can mediate the production of free radicals; foods high in of broad-spectrum botanical defence systems. (These rela- those nutrients are potential oxidants with anti-plasmodial tionships are not unidirectional or otherwise simple, most effects. Dietary Fe over-sufficiency is a proposed adaptation are multitrophic (Dicke 2000). While one species produces in some malaria-endemic areas, where high intake is linked anti-feeding agents and allelo-chemicals, other plants and to cultural practices such as fermenting beer in iron animals evolve mechanisms of chemo-detection, neutrali- containers. Total body stores of Fe and Cu can be further zation and detoxification. Still other organisms have saved affected by Zn, which itself is redox inactive, but it themselves the energy required to maintain elaborate competes with Fe and Cu for binding sites and, thus, chemo-defences by evolving the visual or other organoleptic diminishes the risk of oxidant stress. The potential effects of Fe, Zn and other divalent cations are further mediated by In the larger scheme it makes sense that humans have phytates, tannins and other chelating agents that occur as learned to take advantage of such chemo-defensive ordinary constituents in foods, medicines and other phenomena for their own purposes. The conventional view non-food items (Levander & Ager, 1993; Greene, 1997; of agriculture is that the domestication of plants focused not Adelekan & Thurnham, 1998; Akompong et al. 2000; only on greater yield and ease of harvesting, but also on palatability and diminished toxicity, so that contemporary The oxidant plants mentioned earlier include clove, food cultivars are mere chemical shadows of their wild nutmeg, cinnamon, basil and onion. As these aromatics are counterparts. Recent research illustrates that this is not the both common fever medicines in indigenous pharmaco- case, even the most common foods have great potential to poeias and important flavour principles, anti-malarial influence health beyond the standard nutrient measures of effects can be anticipated. The view that they are vitamins, protein etc. (for example, see Johns, 1996; ‘merely’ spices reflects a Western bias and may overlook Prendergast et al. 1998; Wildman, 2000).
the deliberate addition of these flavourings for theirmedicinal qualities.
Anti-plasmodial oxidant genotypes
Research on Hausa plants in northern Nigeria revealed substantial overlap and suggests that the seasonally- Discussions of the pharmaco-dynamics of drug and food patterned use of oxidant plants in both food and medicine plants typically ignore human biological variability, protects against fulminant malaria infection. Specifically, resonating a biomedical paradigm that projects a generic most of the Hausa plants that demonstrate oxidant and human biology. Stepping outside that template, the model anti-malarial activities are prominent in the diet during the will be expanded once more by noting that elevated eryth- highest malaria risk period (Etkin & Ross, 1997). Building rocyte oxidation not only explains how some anti-malarial on this principle, other researchers have recently begun plants, foods and pharmaceutical agents ‘work’, but also the to explore nutrient-based interventions as low-cost adjuncts adaptive importance of several malaria-protective geno- to current methods of malaria prevention and treatment types. These erythrocyte anomalies are classic examples of (Levander & Ager, 1993; Shankar, 2000).
Darwinian evolution, occurring in high frequency in populations who have experienced considerable selective Haemoglobinopathies and other inherited protections pressure from malaria. While the distribution of these poly- Several haemoglobin disorders also occur as malaria- morphisms is familiar terrain in anthropology and human protective balanced polymorphisms. Haemoglobins S genetics, their shared mode of anti-malarial action is not (sickle cell), C and E are inherited as autosomal recessive widely appreciated. The following discussion juxtaposes structural abnormalities, each allele coding for a single these inherited aspects of malaria protection to the human amino acid substitution in the β chain of the haemoglobin protein. The α- and β-thalassemias are also autosomalrecessive traits, the result of underproduction of either α or β haemoglobin chains respectively. In each case, like Glucose-6-phosphate dehydrogenase deficiency G6PD deficiency, the selective advantage lies with the Glucose-6-phosphate dehydrogenase (G6PD) deficiency is heterozygous individual who is protected against fulminant biochemically the best characterized of the malaria- malaria infection and has no, or fewer, clinical signs protective genotypes. It is inherited as an X-linked recessive associated with the disorder. The anti-malarial effects of gene (tens of alleles are known and are characterized by these erythrocyte anomalies also are explained by elevated similar phenotypes that vary primarily in the extent to which intra-erythrocytic oxidation in infected cells, evidenced by enzyme activity is diminished). As G6PD is the first, high concentrations of methaemoglobin, NAD, NADP and thus rate-limiting, enzyme of the pentose phosphate the oxidized form of glutathione relative to their reduced pathway, low enzyme activity results in cells that cannot counterparts (haemoglobin, NADH, NADH and reduced adequately respond to oxidant stress. In the presence of glutathione), lipid peroxidation and the presence of oxygen malaria infection the integrity of G6PD-deficient erythro- radical species. As in the case of G6PD deficiency, cytes is compromised and parasite development is increased oxidation interferes with parasite development interrupted. Drug-induced erythrocyte destruction in the and survival, accelerates infected erythrocyte clearance more severe G6PD variants was linked first to anti-malarial by phagocytosis and may impede parasite entry into the agents such as primaquine, and has since been expanded to erythrocyte (Chan et al. 1999; Destro-Bisol et al. 1999; embrace oxidant-generating drugs generally. Medicinal and food plants also have been implicated in oxidant erythrocytedestruction and the anaemia that accompanies it (Greene & Conclusion: co-evolution, genetic and cultural
Danubio, 1997; Ruwende & Hill, 1998).
adaptations
Where G6PD is relatively common, this association between consumption of certain plants and anaemia has The erythrocyte abnormalities discussed earlier represent been assimilated into local explanatory models. This the most expensive mode of adaptation, in which protection knowledge allows us to pose interesting questions regarding is conferred on a particular genotype. Conversely, the the cultural construction of G6PD deficiency, malaria and cultural management of medicines and foods is less its treatment. For example, since the earliest recorded expensive in the sense that it is not genetically ‘hard-wired’, history Mediterranean variants of G6PD deficiency have but changeable and reversible within one lifetime. Culture been linked to ‘favism’, a severe haemolytic reaction to affords us considerably more flexibility in achieving oxidants in fava beans (Vicia fava L., Fabaceae). In therapeutic and preventive objectives. In the case of some populations food taboos prohibit G6PD-deficient managing oxidant medicines and foods, human cultures individuals from eating fava beans because of their have refined the biological templates represented by G6PD association with anaemia. Similarly, for high-risk groups deficiency and the malaria-protective haemoglobinopathies.
like children, fava beans are prepared by removing the seed In eventually developing pharmaceutical agents such as coat, which contains the highest concentration of oxidants.
primaquine, humans duplicated the folk therapeutic models Fava beans are also used medicinally; the malaria-protective based in oxidant plants, which are themselves molecular effects of G6PD deficiency can be potentiated by fava consumption, and for G6PD-normal individuals the In the scientific literature oxidation is typically portrayed cultivation of fava beans is deliberately configured so that as detrimental; for example, its roles in carcinogenesis and consumption coincides with periods of peak malaria risk.
cardiovascular disease are emphasized. This knowledge has In this way both enzyme-deficient and enzyme-normal been transposed in abbreviated form to the lay public, many individuals are afforded protection through increased eryth- of whom know they want antioxidants, although they are rocyte oxidation due to ingestion of fava beans. Oxidant not sure why. Various lines of inquiry that converge to plants recognized in other cultures where G6PD deficiencies demonstrate the benefit of oxidation in malaria prevention occur are also subject to customs that govern who can or and therapy have been presented. The characterization of cannot use that species, how it should be harvested and oxidants, their basis in the chemical defences of plants and prepared, and the timing of consumption. In another cultural their interaction with malaria offers insights into the spin some Chinese populations divide medicinal plants into complexity of malaria prevention and cure.
cold or yin oxidant species and hot or yang antioxidants (Lin This discussion offers a theoretical perspective for et al. 1995). In both the Mediterranean and Chinese understanding how medical cultures mediate the inter- examples cultural dicta have a bearing on the biophysiology section of co-evolutionary modes that involve humans, of both G6PD deficiency and the various plants that interact plants, herbivores and all their respective pathogens.
Ultimately, this perception allows us to appreciate that human adaptation to malaria is complex and profoundly Greene LS (1997) Modification of antimalarial action of oxidants in biocultural. On the practical side this insight suggests a traditional cuisines and medicines by nutrients which influence paradigmatic shift in the way that plants can be evaluated for erythrocyte redox status. In Adaptation to Malaria: the anti-malarial potential. On a more abstract level, following Interaction of Biology and Culture, pp. 139–176 [LS Greene and the theme of oxidation, we see continuity in the face of a ME Danubio, editors]. New York: Gordon and BreachPublishers.
shifting dynamic of biology and culture, stretching back as Greene LS & Danubio ME (editors) (1997) Adaptation to Malaria: the Interaction of Biology and Culture. New York: Gordon andBreach Publishers.
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