This paper investigated whether Artemisinin annua was the way forward in tackling the increasing problem of malaria. It focussed on ways to increase the yield of A. annua whilst helping farmers in less economically developed nations bring socioeconomic benefits. It was found that using Whole Plant A. annua was more beneficial than using pure drug Artemisinin in terms of malaria control. It was clear that more money needs to be spent to understand A. annua as a plant and the best way to increase the yield.
Finding ways to reduce the risk of malaria, especially in developing countries is becoming increasingly important. The Chinese medicinal plant Artemisinin annua L. is central in finding successful ways to control malaria. A. annua is a plant that produces low yields, which is detrimental in the fight against malaria. This paper reviews possible ways of increasing the yield of A. annua using herbal tea extract and whole plant therapy, whilst also exploring other methods of mosquito population control, such as the Sterile Insect Technique and the release of Insects Carrying a Dominant Lethal Gene. Malaria is a devastating disease affecting thousands of people each day, mostly children in sub-Saharan Africa. It is carried by mosquitoes, four of which can cause malaria in humans. New methods of controlling malaria are urgently needed, as the overall global temperature increases which increases the risk of malaria.
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There are four parasite species that cause malaria in humans. Plasmodium falciparum and Plasmodium vivax are the most common; however Plasmodium falciparum is the most deadly (Dalrymple et al. 2012). The malaria parasite is transmitted to the female mosquito from an infected individual as a blood meal is taken. The first blood meal is a prelude to reproduction. After a blood meal, the parasite undergoes a life cycle change before it is able to become infectious. As the temperature of the environment decreases, the period required for this life cycle change increases and transmission of the parasite becomes less likely as the environmental temperature falls below 16°C. At low temperatures, many species of mosquito suspend biting meaning the stability and transmission of malaria is greatly reduced in temperate regions (Sachs and Malaney 2002). Sub-Saharan Africa is the largest sanctuary of Plasmodium falciparum, the most lethal of the protozoan parasite species causing malaria in humans. It is also the home of Anopheles gambiae, the most aggressive of the species of mosquito currently transmitting malaria to humans (Dunavan et al. 2005). The high transmission rates in sub-Saharan Africa reflect the large capacity of Africa's main vector carrying mosquito A. gambiae complex of species, with their high tendency towards anthropophily (Sachs and Malaney 2002).
The Economic and Social Burden of Malaria
Malaria is one of the top three killers amongst communicable diseases (Sachs and Malaney 2002). In 2010, malaria caused an estimated 665,000 deaths, mostly to children in sub-Saharan Africa (Dalrymple et al. 2012). The World Health Organisation (WHO) estimated that in 2009, 225 million cases of malaria occurred with >780, 000 deaths (Elfawal et al. 2012). Malaria causes fever and chills, anaemia, seizures, heart and lung failure and often death (Dunavan et al. 2005). The increased prevalence of malaria in recent years could be due to population movements into malaria dense regions and changing agricultural processes. In the long term, climate change and the El Niño Southern Oscillation could both be factors in increasing malarial resistance to drugs and insecticides. Malaria has become so prevalent in some regions of sub-Saharan Africa that genetic mutations such as sickle-cell trait are being selected for as protection against malaria. Sickle-cell trait provides protection from malaria when it is inherited from one parent however is fatal if inherited from both parents. The chance of death from malaria is so high in some regions of sub-Saharan Africa that it justifies welcoming a potentially fatal genetic mutation into the gene pool, due to the fact that it provides some protection to the increasingly prevalent malaria transmission.
Artemisinin-based combination therapies (ACTs) are one possible malarial treatment (Mutabingwa 2005). The main issue with the use of Artemisinin is producing enough to meet world demand (Milhous and Weina 2010). A study of this therapy (Mutabingwa, 2005) explores the option of using ACTs. In 2005, ACTs were the best anti-malarial drugs available. They had been shown to successfully reduce the overall malarial transmission, but only at low intensities. In 2005, alternative ways for increased production of ACTs were desperately needed, but had not yet been discovered. ACTs have been known to reduce overall malarial transmission through action of viability of gametocytes, leading to reduced infectivity of mosquitoes. Early treatment was needed as ACTs have a gametocidal effect on stages one to three, but not on stage four. It was concluded that more effective controls were Insecticides and Insect Treated Nets (ITNs) (Mutabingwa 2005).
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A study of the genetic map of Artemisia annua L. (Graham et al. 2010) confirmed that parasite resistance to A. annua had been found in western Cambodia. The increasing problem of artemisinin resistance was best addressed by increasing the availability of ACTs. Funding for ACTs increased and yet the supply chain was unable to produce high quality artemisinin in the quantities that were required, meaning the supply of ACTs was left reliant on the agricultural production of artemisinin. Plant based production was challenging, as at the time, A. annua was undeveloped as a crop. An alternative method of production was hypothesised, that of a microbial-based system that was able to synthesise an artemisinin precursor for chemical conversion. This was in development as a supplement to agricultural production, as agricultural production needed to continue being that it was an essential source of supply (Graham et al. 2010).
Comparison of the in-vitro activity of A. annua herbal tea and artemisinin was carried out (De Donno et al. 2012). A. annua tea had previously been proven to be an effective treatment for malaria. The effects of A. annua tea were tested on Plasmodium falciparum cultures in-vitro against chloroquinine (CQ)-sensitive D10 and CQ-resistant W2 strains of P. falciparum using the parasite lactate dehydrogenase assay. Results of the tests carried out were consistent with the efficacy of A. annua tea [50% inhibitory concentration for strain D10= 1.11 0.21 µg/ml; IC50 for strain W2 = 0.88 0.35 µg/ml]. In this particular experiment, the concentration of artemisinin in A. annua tea (0.18 0.02% of dry weight) was shown to be far too low to be responsible for any anti-malarial activity. This does not correspond with previous results and research on this topic. It was therefore thought to be likely that the artemisinin in the tea co-solubilised with other ingredients (some of which may provide protection from malaria) to produce anti-malarial activity.
In another experiment (Elfawal et al. 2012) it was suggested that dried whole plant A. annua could be used as an anti-malarial therapy. ACTs are currently thought to be the best treatment against malaria parasites that have evolved resistance to chloroquinine. Production of artemisinin for this experiment required extraction from the cultivated herb A. annua. The drug was extracted from plant material, crystallised and used for the semi-synthesis of artemisinin derivates. This experiment omitted the extraction step, saving time and money, by using A. annua directly as a source of artemisinin. It was shown that mice which were fed dried WP material had up to 40x more artemisinin in their bloodstream than mice which were fed corresponding amounts of the pure drug. Active ingredients were delivered faster and in greater quantities from WP treatments than from the pure drug. Orally digested powdered dried leaves of WP A. annua were able to kill malaria parasites more effectively than pure artemisinin. Dried A. annua leaves which contained 14.8mg artemisinin per gram were used, and parasitemia was compared over time in mice treated with low-dose WP A. annua, low-dose pure artemisinin or placebo. After 24 hours, dead parasites were seen in mice treated with low-dose WP A. annua. Mice treated with low-dose WP A. annua showed significantly lower parasitemia than those treated with low-dose pure artemisinin and those treated with low-dose pure artemisinin did not show a significant difference in parasitemia from those treated with the placebo (Elfawal et al. 2012).
The Sterile Insect Technique (SIT) does not rely on A. annua. It is a species specific and environmentally benign method for insect population control. An experiment was carried out that involved mass rearing, radiation mediated sterilization and the release of male insects into a target area. Successful mating meant no offspring were produced and the population declined. This reduced the transmission of vector borne diseases. Males are good at seeking out females of the same species and as the population declines, the technique becomes more effective. It is the most non-disruptive pest control method, as it is species specific and does not release exotic agents into new environments. However, the released sterile insects have to compete for females with wild males already in the environment. The success of the SIT relies on the release of a large number of insects, which can be costly (Wilke and Marrelli 2012). There have been some successful SIT programs that eliminated and suppressed pests, but not specifically mosquitoes. In the case of mosquitoes, in the 1970's and 1980's twenty field trials were carried out that demonstrated the capacity of the Sterile Insect Technique in controlling the numbers of malaria carrying mosquitoes. Anopheles albimanus was successfully controlled in a field trial using chemo-sterilized mosquitoes. The use of SIT against malaria carrying mosquitoes is problematic, mainly due to the operational difficulty involved with exposing the mosquitoes to radiation and the density dependent nature of the target populations.
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The release of Insects Carrying a Dominant Lethal Gene, or RIDL (Wilke and Marrelli 2012) was thought to be an improvement on the Sterile Insect Technique. The system involved introducing a lethal dominant gene that was controlled by a female-specific promoter. Expression of the lethal gene was inactivated by treatment with tetracycline, which allowed the colony to be maintained. When males and females were separated the tetracycline was removed which caused the death of female mosquitoes. The RIDL system is centred on the expression of tTa, a fusion protein that combines sequence- specific tetracycline-repressible binding of tRe to a eukaryotic transcriptional activator. In the absence of tetracycline, the protein binds to the tRe sequence, activating transcription from a nearby minimal promoter, as shown in figure 1 (Wilke and Marrelli 2012).
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Figure 1 shows tTa and the tetracycline-repressible expansion system.
When the mosquitoes were prepared for release, the repressor was inactivated and the lethal gene was expressed, which caused the death of all females. RIDL offers a solution to many of the drawbacks of the traditional system of SIT (Wilke and Marrelli 2012).
With respect to the A. annua tea experiment, further research in this area would be needed to determine whether the presence of anti-malarial compounds in A. annua tea hinders the development of parasite resistance compared with pure artemisinin (De Donno et al. 2012). This study was only carried out on Plasmodium falciparum. For more reliable results, the same test would need to be carried out on more species. The efficacy of the tea has also not been investigated in vitro; this would need to be carried out to obtain better results.
It was concluded that orally delivered WP A. annua was effective in killing malaria parasites in a mouse model. As the genetic makeup of mice is similar to that of humans, this was a positive start. To produce more conclusive results however, orally delivered WP A. annua needs to be tested on humans with malaria to see if the results produced are conclusive. An edible WP A. annua treatment approach could significantly reduce costs of treatment. WP treatment is a more efficient delivery mechanism than purified A. annua, which is costly and inefficient. Using a high dosage treatment provides potential resistance against many infectious agents, meaning the approach outlined in this review would dramatically reduce costs of healthcare across many nations. A. annua production could also be implemented globally, focusing on plant cultivation and processing, providing socioeconomic stimulus for the countries growing the crop.
There is still much interest in the use of SIT as a method of mosquito control, with many research groups trying to overcome the difficulties associated with SIT which stopped it from becoming a widely used approach following early trials (Wilke and Marrelli 2012). RIDL offers a solution to the drawbacks of SIT, as all female mosquitoes are killed when tetracycline is removed and the repressor is inactivated. Much more research needs to be done into this area to conclude whether it is a viable alternative to using A. annua to control malaria.
If using orally delivered WP A. annua is seen as the most effective way of controlling malaria, more research needs to be carried out as to how to increase the yield of A. annua, especially making it possible for farmers in less economically developed nations to grow the crop, providing a much needed boost to their economy, as well as controlling malaria in the community.