TRANSMISSION BLOCKING STRATEGY FOR MALARIA ERADICATION: THE ROLE OF ANTIMALARIAL AGENTSHTML Full Text
TRANSMISSION BLOCKING STRATEGY FOR MALARIA ERADICATION: THE ROLE OF ANTIMALARIAL AGENTS
T. O. Johnson
Department of Biochemistry, Faculty of Medical Sciences, University of Jos, Nigeria.
ABSTRACT: Elimination and Eradication is an important component of the Global Strategy for combating malaria, and one of the ways of achieving this purpose is blocking the transmission of malaria parasites from humans to mosquito vectors. The ability of Plasmodium to cease asexual replication in the erythrocytes of the human host and commit to the formation of gametes necessary for sexual replication in the gut of the mosquito vector is essential for efficient transmission of malaria. Although a conserved member of the Apicomplexan AP2 family of transcriptional factors acts as the master switch in triggering the transcriptional cascade that initiates gametocytogenesis, some environmental factors including some antimalarial drug treatments, are believed to switch on the gene(s) that determine the commitment to the sexual phase. Antimalarial agents have different effects on gametocyte carriage depending on their mechanisms of action. This review enumerates the role of various classes of antimalarial agents in either promoting or preventing plasmodium gametocytogenesis and points out the need to, in addition to exiting gametocytocidal, design new drugs that are capable of preventing gametocytogenesis and killing mature gametocytes in humans; or preventing gametogenesis and fertilization in the mosquito.
Malaria, Gametocytogenesis, Chloroquine, Primaquine, Artemisinin, Antifolates
INTRODUCTION: Malaria is afebrile, mosquito-borne infectious disease of humans, caused by eukaryotic protists of the genus Plasmodium. It is prevalent throughout most of the tropical world. Globally, an estimated 3.2 billion people in 97 countries and territories are at risk of being infected with malaria and developing the disease, and 1.2 billion are at high risk (>1 in 1000 chance of getting malaria in a year). According to the latest estimates, 198 million cases of malaria occurred globally in 2013, and the disease led to 584 000 deaths 1.
Even though these represent a decrease in malaria case incidence and mortality rates of 30% and 47% since 2000, respectively 1, malaria is still one of the ‘big three’ diseases, along with HIV and tuberculosis, affecting the developing world. While it has been eliminated in many regions, it remains a scourge of poorer countries 2, hence the need for continued efforts in the fight against this deadly disease. The early signs of resistance to existing antimalarial drugs shown by the parasites are gradually becoming a major concern, and the World Health Organization (WHO) warns that the public health consequences could be dire 3.
The Malaria Eradication Research agenda initiative, created in 2007 have re-established the long-term goal of malaria eradication 4. One way of achieving this goal is the transmission-blocking strategy aimed at the identification of therapies capable of eliminating Plasmodium gametocytes, the sexual forms of the parasites that are transmitted between humans and Anopheles mosquitoes 5. However, considerable increases in gametocyte prevalence have been observed after widespread use of some antimalarial therapies 6. Drug-induced gametocytogenesis has been investigated in some clinical studies 7, but it has been difficult to draw firm conclusions from these studies. It is, however, clear that gametocytemia is a very sensitive indicator of emerging drug resistance 8, with increasing gametocyte prevalence having been shown to precede measurable changes in parasite clearance or a decrease in cure rates 9. To eradicate malaria, it is highly necessary to monitor the effects of antimalarial chemotherapy on gametocyte carriage and to identify or design new drugs that promote gametocytocidal activity 9.
Plasmodium Life Cycle: The malaria parasite exhibits a complex life cycle involving an insect vector (mosquito) and a vertebrate host (human). The major phases of the life cycle are a liver stage, blood stage, sexual stage, and sporogony Fig. 1.
FIG. 1: LIFE CYCLE OF MALARIA PARASITE 10
Sporozoites are inoculated into the human with the bite of a female Anopheles mosquito, they migrate immediately to the liver and invade hepatic cells. Sporozoites undergo an asexual replication known as exoerythrocytic schizogony during a dormant period of approximately two weeks to form schizonts and cause rupture of the hepatocytes. A hepatocyte releases up to 30 000 merozoites, each capable of invading an erythrocyte. However, a proportion of the liver-stage parasites from P. vivax and P. ovale go through a dormant period instead of immediately going through the asexual replication. These hypnozoites reactivate after several weeks to months (or years) after the primary infection and are responsible for relapses.
The invasion of erythrocytes by merozoites begins a period of asexual cycling in the erythrocytes. The invading merozoites undergo a trophic period in which the parasite enlarges. The early trophozoite is often referred to as 'ring form' because of its morphology. Trophozoite enlargement is accompanied by an active metabolism including the ingestion of host cytoplasm and the proteolysis of hemoglobin into amino acids. The parasite avidly ingests and degrades host erythrocyte hemoglobin using a specialized structure called a cytostome11-15, which spans the double membrane between erythrocyte and parasite cytoplasm. Hemoglobin-containing vesicles are pinched off from the cytostome and travel to the digestive vacuole where the hemoglobin is broken down 12, 13, 15-17. The process of hemoglobin degradation releases heme, which is detoxified by polymerization into a crystalline pigment, hemozoin 18, 19.
Multiple rounds of nuclear division manifest the end of the trophic period without cytokinesis resulting in a schizont. Merozoites bud from the mature schizont also called a segmenter, and the merozoites are released following rupture of the infected erythrocyte. Invasion of erythrocytes reinitiates another round of the blood-stage replicative cycle. A single merozoite invading a cell is capable of producing as many as 36 merozoites in a mature multinucleated schizont. On average in P. falciparum, 16 new merozoites are released from an erythrocyte every 48 h, each of which can invade a new cell. The resultant exponential increase in parasitemia is mainly responsible for the onset of clinical symptoms 20.
At a point during the multiple rounds of asexual erythrocytic cycling, a proportion of parasites are stimulated to differentiate into sexual forms known as macro- (female) and micro- (male) gametocytes. The transmission of malaria parasites from man to mosquito depends on the presence of mature Plasmodium gametocytes in the human peripheral blood. P. falciparum gametocytes undergo complex development that is characterized by five morphologically distinct stages (I–V). Only mature stage V gametocytes are observed in the peripheral blood and are accessible to feeding mosquitoes. Once ingested by a feeding female Anopheles mosquito, male and female gametocytes form gametes that fuse to form zygotes that develop into a motile ookinete that can penetrate the peritrophic membrane and traverse the mosquito midgut epithelium to form oocysts. The oocysts enlarge over time and rupture to release sporozoites that migrate to the mosquito salivary glands. Once the sporozoites have migrated into the salivary glands, the mosquito is infectious to humans 21.
Parasite Commitment to Gametocytogenesis: The ability of Plasmodium to cease asexual replication in the erythrocytes of the human host and commit to the formation of gametes necessary for sexual replication in the gut of the mosquito vector is essential for efficient transmission of malaria. Differentiation of some of the parasites in the human bloodstream into sexual forms that can mate inside the mosquito is the key to this commitment. It has been reported that, in P. falciparum, commitment to sexual stage occurs one cycle before gametocytes appear in the blood, such that all merozoites released from a single schizont are already committed for following either a sexual cycle or an asexual one 22, 23. This implies that the trophozoites of the preceding asexual cycle were already committed to follow either a sexual or an asexual cycle 23. Also, all merozoites from a “sexually committed” schizont become either males or females 24, 25. That would indicate that commitment to male or female gametocytes either happens concomitantly or follows the asexual-to-sexual switching 26.
The molecular basis of the developmental switch – the “Holy Grail” for understanding gametocytogenesis has eluded the malaria research community for years. However, recent reports by the teams of Oliver Billker (Wellcome Trust Sanger Institute), Manual Llinás (Princeton and Penn State Universities) and Andy Waters (Glasgow University) provide resounding evidence that a conserved member of the Apicomplexan AP2 family of transcriptional factors acts as the master switch in triggering the transcriptional cascade that initiates gametocytogenesis. The AP2 master switch, termed AP2-G (for gametocytogenesis), was discovered in both human malaria P. falciparum and mouse malaria P. berghei (mouse malaria). A second AP2 transcription factor, termed PbAP2-G2, was also identified in P. berghei as necessary for gametocytogenesis, although not acting in a master switch role 27-29.
Although the molecular switch has been identified, what throws that switch, releasing AP2-G from its silenced state and making some malaria patients into ‘transmitters’ while others are not, is still a mystery. However, in P. falciparum and berghei, there is evidence that the switching mechanism is highly flexible and is responsive to primary signals which include certain environmental factors which are believed to switch on the gene(s) that determine the commitment to the sexual phase 30, 31. The decision to commit to sexual development is, therefore, a multifactorial one, based on an intricate relationship between environmental stimuli and developmental pathways acting on stage-specific genes. Although the mechanisms involved remain poorly understood, it is generally accepted that conversion to a gametocyte occurs when environmental conditions no longer favor asexual growth.
Environmental factors implicated in gametocytogenesis could be grouped as those contributed by the host or the parasite, or could simply include a drug treatment or a signaling mechanism 23. Various host factors contributing to increased commitment to gametocytogenesis include increased immune pressure 32-34, increased steroids and corticosteroids 35, an increased proportion of reticulocytes in blood 36, 37 and anemia 38, 39. Antimalaria drugs were also found to induce gametocytogenesis 40, 23. Many parasite-borne factors have been demonstrated which affect gametocytogenesis. These include the presence of mixed-genotype infections 41, 42, levels of asexual parasitemia 30 and occurrence of lysed parasitized erythrocytes 43. These environmental triggers strongly suggest a signal transduction mechanism through which the parasite receives a cue to sexual commitment. G proteins have been implicated as a signaling mechanism to mediate the switching to sexual development in response to environmental stimulus 30.
Role of Antimalarial Agents in Gametocytogenesis: Various reports have shown the effects of antimalarial agents on the development, density, and intensity of gametocytes. Peatey et al., used transgenic Plasmodium falciparum parasites expressing a green fluorescent protein tag in a fluorescence-activated cell sorting-based assay to measure the effect of 8 antimalarial drugs (chloroquine, quinine, atovaquone, artemisinin, mefloquine, primaquine, piperaquine, and pyronaridine) on gametocyte production in-vitro. Exposure to antimalarial drugs increased the number of gametocytes in test cultures 44. However, Artemisinin derivatives combination therapy 45-47 and primaquine 48 are gametocytocidal and to reduce transmission.
A trend towards the decreased expression of genes involved in glycolysis, protein biosynthesis and hemoglobin catabolism observed in later gametocyte stages 48 have been reported to correspond with the absence or reduced gametocytocidal activity of antimalarial drugs targeting some of these processes. Some inhibitors of nucleic acid synthesis 49 including antifolates50 and Chloroquine 40 have been shown to increase the rate of gametocytogenesis. These suggest that the effect of an antimalarial drugon gametocytogenesis depends of its mechanism of action.
Quinolines: Several studies have indicated that quinolines Fig. 2 such as chloroquine, mefloquine, quinine, and quinidine act against the erythrocytic stage of infection by inhibiting polymerization of the heme that is released during hemoglobin degradation. Primaquine, however, kills intrahepatic forms and gametocytes. Quinine, the first of all antimalarials extracted from the bark of the South American Cinchona spp tree, is reported to be a powerful schizonticide, active only against malaria pigment (hemozoin) producing stages 51. The drug has no activity against the sporozoites and exo-erythrocytic stages of the parasites (liver schizonts) which do not consume hemoglobin. Other blood schizontocidal antimalarial drugs (chloroquine, amodiaquine, mefloquine, halofantrine, and lumefantrine) are suggested to be inhibitors of heme detoxification 52, a property which has been suggested to cause inhibition of asexual growth and subsequent increase in gametocytogenesis 53-58. Buckling et al., demonstrated a 5-fold increase in gametocytogenesis in human malaria, P. falciparum, in-vitro, in response to treatment with chloroquine. In all clones used, gametocytogenesis increased with increasing inhibition of asexual growth by chloroquine 40.
FIG. 2: STRUCTURES OF SOME QUINOLINES 59
Chloroquine-induced gametocytogenesis has been linked with the prevalence of drug resistance. Several studies have found that the proportion of chloroquine-treated patients harboring gametocytes is higher among those presenting therapeutic failures than patients with adequate therapeutic response 60-62. This suggests that resistant parasites are more likely to develop gametocytes after treatment, thereby favoring the spread of drug resistance 63.
Primaquine, an 8-aminoquinoline, has no sporontocidal effect on P. falciparum 64 but has been known to reduce the prevalence of gametocytes circulating in the peripheral bloodstream of infected individuals and to prevent exflagellation in gametocytes that are present 65.
FIG. 3: STRUCTURE OF PRIMAQUINE 66
Primaquine is metabolized via oxidative deamination at the C-4’ into its primary metabolite carboxyprimaquine which displays much reduced antimalarial activity 67, 68. Other metabolites vary in their antimalarial activity, with 5,6-dihydroxy-8-aminoquinoline showing relatively intense in vitro inhibition of P. berghei exoerythrocytic stages while 6-hydroxy-8-aminoquinoline is even less active than carboxyprimaquine 68. Acylation of the aliphatic side-chains of primaquine derivatives effectively blocks their conversion to carboxyprimaquine, extending their activity. Further development of primaquine derivatives was however discouraged due to diverse interactions between primaquine and G6PD-deficient (G6PDd) individuals. Toxic metabolites of primaquine including 5-hydroxyprimaquine and 6-methoxy-8-aminoquinoline 69 may induce severe hemolytic anemia by oxidizing glutathione to glutathione disulfide which leaches from red cells and leads to denatured, insoluble aggregates of hemoglobin in intact cells that are then preferentially removed from circulation by the spleen and liver 48, 70.
However, WHO has conducted a review of the evidence on the safety and effectiveness of primaquine as gametocytocide of P. falciparum, which indicates that a single 0.25 mg base/kg is effective in blocking transmission and is unlikely to cause serious toxicity in subjects with any of the G6PD variants 71.
Antifolates: The antifolate drugs used against malaria include various combinations of dihydro- folate-reductase inhibitors (proguanil, chlorpro-guanil, pyrimethamine, and trimethoprim) and sulfa drugs (dapsone, sulfalene, sulfamethoxazole, sulfadoxine, and others) 72 Fig. 4.
FIG. 4: STRUCTURES OF SOME ANTIFOLATES 59
Antifolates are thought to act against the parasite by inhibiting the synthesis of folate, as they do in bacteria, although few studies have been performed to determine whether this is truly their mechanism of action 73. Pyrimethamine and cycloguanil are suggested to target the dihydrofolate reductase (DHFR) activity of the parasite's bifunctional DHFR-thymidylate synthetase (TS) protein, whereas the sulfa drugs affect the dihydropteroate synthetase (DHPS) activity of the bifunctional hydroxymethylpterin pyrophosphokinase (HPPK)-DHPS protein, all of these drugs acting as competitive inhibitors of the natural substrates. DHPS found only in the parasite, participates in the de novo synthesis of essential folate coenzymes. DHFR, present in both host and parasite is required for the maintenance of a constant supply of fully reduced (tetrahydro) forms of folate for essential one-carbon transfer reactions, including the provision of nucleotides for DNA synthesis 74.
The antifolate antimalarial, pyrimethamine-sulfadoxine (Fansidar), has become increasingly used as first-line treatment of malaria in several African countries because of increasing resistance in Plasmodium falciparum to chloroquine. With increased use, resistance in P. falciparum to this drug has also increased 75. It was later suggested that co-trimoxazole, an antifolate antimalarial with relatively short half-lives of its components compared to pyrimethamine-sulfadoxine, may be used as an alternative to the latter for the treatment of uncomplicated falciparum infections in children, because it is equally effective 76, 77.
Nevertheless, however, these drugs have been found to significantly increase the prevalence and intensity of gametocytaemia during acute malaria infections in children from a hyperendemic area in Southwestern Nigeria.
The effect was more pronounced in children treated with pyrimethamine-sulfadoxine than in those treated with co-trimoxazole78. Puta and Manyando reported an enhanced gametocyte production in Plasmodium falciparum malaria patients treated with Fansidar 79. The very high post-treatment prevalence and density of gametocyte carriage following pyrimethamine-sulfadoxine treatment have been reported to contribute to the remarkable spread of its resistance across vast regions 80.
Artemisinin Derivatives: Artemisinin (Qinghaosu), one of the most potent and effective antimalarials to date, discovered by Chinese chemists in the 1970’s; ‘project 523’ 81 are effective not only against multi-resistant strains of P. falciparum, but have broad stage specificity against the Plasmodium life cycle including activity throughout the asexual blood stages 82 and also the sexual gametocyte stages 83. Artemisinin is a sesquiterpene trioxane lactone whose endoperoxide bridge is essential for antimalarial activity. Semisynthetic derivatives of artemisinin include Artesunate, artemether, dihydroartemisinin, artelinic acid and artemoti 84 Fig. 5.
FIG. 5: STRUCTURES OF ARTEMISININ AND DERIVATIVES 85
The cleavage of the peroxide bridge of artemisinin in the presence of ferrous ion (Fe2+) from heme derived from the breakdown of the host cell hemoglobin by the parasites, forms highly reactive free radicals which rapidly rearrange to more stable carbon-centered radicals 86, 87. These artemisinin-derived free radicals have been suggested to chemically modify and inhibit a variety of parasite molecules, resulting in parasite’s death 88, 89. A more recently described alternative is that artemisinins disrupt cellular redox cycling 90.
Artesunate has been shown to potently inhibit the essential Plasmodium falciparum exported protein 1 (EXP1), a membrane glutathione S-transferase 91. Recently Shandilya et al. suggested a free radical mechanism where artemisinin gets activated by iron present in food vacuole which in turn inhibits PfATP6 by closing the phosphorylation, nucleotide binding and actuator domains leading to loss of function of PfATP6 of the parasite and its death 89, 92-95.
Artemisinins act primarily on younger gametocytes 96, 97, inhibiting differentiation to the mature infective stages. ACTs also shorten the typical carriage of gametocytes in the blood from 55.6 days in patients receiving non-ACT therapies to 13.4-28.6 days in those receiving ACTs 98. Certain studies, however, have demonstrated activity against mature gametocytes in-vitro 99, 100, though this effect does not appear to translate to significant clinical impacts against mature gametocytes in infected patients 48.
Single Dose Primaquine with an ACT: As stated earlier, artemisinin is an effective antimalarial, but its activity is limited to asexuals and stage I-III gametocytes. Furthermore, clinical resistance to artemisinin-based combinations (ACTs) has been recently reported in Cambodia 101. Primaquine is the only drug currently available that is effective against stage V gametocytes, and its use as a gametocytocide has great potential to reduce the transmission of falciparum malaria in low transmission settings, and in particular to help contain the spread of artemisinin-resistant falciparum malaria in Southeast Asia. The main limitation to its use has been hemolytic toxicity. The 8-aminoquinoline antimalarials produce dose-dependent acute hemolytic anemia (AHA) in individuals who have G6PD deficiency, an inherited X-linked abnormality.
WHO has conducted a review of the evidence on the safety and effectiveness of primaquine as gametocytocide of P. falciparum. Based on this review, the Malaria Policy Advisory Committee (MPAC) recommends the following: In: (1) areas threatened by artemisinin resistance where single dose primaquine as a gametocytocide for P. falciparum malaria is not being implemented, and (2) elimination areas which have not yet adopted primaquine as a gametocytocide for P. falciparum malaria: A single 0.25 mg base/kg primaquine dose should be given to all patients with parasitologically-confirmed P. falciparum malaria on the first day of treatment in addition to an ACT, except for pregnant women and infants less than 1 year of age 71.
CONCLUSION: A malaria-free world is achievable. Discovery and use of new antimalarials with activities against both the asexual and sexual stages of the parasites could prevent transmission of malaria parasites from humans to mosquito vectors.
AKNOWLEDGEMENT: My special gratitude goes to the main Library, University of Jos, Nigeria, for providing free access to the resource materials used while writing this review, and to the Department of Biochemistry, as well as the African Centre of excellence in Phytomedicine Research and Development (ACEPRD), University of Jos, Nigeria, for providing a good platform for teaching and research.
CONFLICT OF INTEREST: Nil
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How to cite this article:
Johnson TO: Transmission blocking strategy for malaria eradication: the role of antimalarial agents. Int J Pharmacognosy 2015; 2(10): 484-93. doi: 10.13040/IJPSR.0975-8232.2(10).484-93.
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