Plasmodium Falciparum Control Strategies

Plasmodium Falciparum Control Strategies

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International effors to address Plasmodium falciparum, a protozoan parasite that causes malaria, have been ongoing since the 1940s and 1950s¹². Over half of the world's population is at risk for getting infected with Plasmodium falciparum, thereby contracting malaria¹.
Malaria is a deadly disease and is estimated to be endemic in over 100 different countries¹. It is also the cause of approximately one million deaths every year¹.

Introduction

Background

The Plasmodium falciparum parasite lives in blood, and is of the genus Plasmodium. There are over 200 different Plasmodium species, but only 11 known types actually infect humans. Of the different species, Plasmodium falciparum is the most dangerous to humans, because it has very high mortality rates².

This image shows a female Anopheles gambiae mosquito feeding on the blood of a human. The picture was taken by an employee of the Centers for Disease Control and Prevention. [1]

The main vector for the spread of the Plasmodium falciparum parasite is mosquitoes². There are many types of mosquitoes, but only a subset suck blood; of those, only some species are malaria transmitters. The mosquito species Anopheles gambiae (pictured at right) is one of the most efficient malaria vectors known because it transmits Plasmodium falciparum².

Spread and Life Cycle

The Plasmodium falciparum parasite population requires both human hosts and mosquito vectors in order to perpetuate. The life cycle of P. falciparum, depicted at the left, occurs as follows:¹¹

Mosquitoes acquire the P. falciparum parasite at first by ingesting blood from an infected human. The parasite reproduces when it enters the mosquito gut, and spreads to its salivary glands. When a mosquito punctures the skin of a human, the Plasmodium falciparum parasite enters the bloodstream by being released from the salivary glands of the mosquito.

Lifecycle of Malaria. [2]

Upon entering the bloodstream, the P. falciparum is in sporozoite form. The sporozoites make their way to the liver, where they infect liver cells and multiply. They are then released into the bloodstream as merozoites, where they can infect red blood cells and reproduce asexually. As the cycle continues, infection spreads from human to human.

Effect on Mosquitoes

Plasmodium falciparum can cause behavioral changes in the mosquitoes that carry it.⁴ A mosquito that has acquired the P. falciparum parasite, is more inclined to feed off of a greater number of individuals in a night, and suck more blood in a single feeding than a mosquito without the parasite. This phenomenon increases the ability of Plasmodium falciparum to spread quickly through mosquitoes.

Control Strategies

There are no effective vaccines for malaria, since infected individuals don't obtain complete immunity to the infection. Any long-lasting immunity to malaria usually requires repeated exposure to the parasite². The difficulty in creating any effective immunization is due to the parasite's ability to change the antigens it presents, which are the targets for protective antibodies². The P. falciparum genome actually encodes fewer enzymes and transporters than other free-living eukaryotic microbes, but it encodes a high proportion of genes dedicated to evading immune responses and host-parasite interactions ³. There are drugs which have been used to effectively treat malaria after an infection has already occured. These include chloroquine, primaquine, and artemisinin-based combination therapy (ACT)^2.

Since is not possible to completely immunize at-risk individuals, the focus of malaria prevention is on reducing or controlling the spread of the disease. Research on the microbial interactions of Plasmodium falciparum and its vector, Anopheles gambiae, reveals possible approaches for malaria control, including use of the [natural mosquito immune response], [environmental factors which affect the proliferation of P. falciparum in mosquitoes], and the [introduction of new bacteria to mosquitoes].

Natural Anopheles Gambiae Immune Response

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This photomicrograph from the Centers for Disease Control depicts the Plasmodium falciparum parasite only a few minutes after a mosquito ingests the parasite's gametocytes. [3]

One possible avenue for controlling the spread of Plasmodium falciparum is by way of the natural A. gambiae immune response. When Plasmodium falciparum enters a mosquito, there is a systematic response, specific to the type of Plasmodium species infecting the mosquito⁵. A study in 2002 revealed that the presence of P. falciparum actually regulates and triggers the amount of defensive gene expression occuring in mosquitoes⁵. The different immune responses that occur are specific to the stage of the Plasmodium falciparum infection. One of the components of the immune response system is transmembrane PGN Recognition Protein LC, which is a peptidoglycan receptor that senses the presence of infections in a mosquito's blood or gut. It is able to activate a signaling pathway that drastically reduces the proliferation of microbes in mosquito guts, along with infections from P. falciparum⁶. An understanding of the details of mosquito immune responses to Plasmodium falciparum could be used to produce mosquitoes that are resistant to infection, in order to fight the spread of Plasmodium falciparum.

Bacterial Regulation By Environmental Influences

There have been several studies which focus on the interaction of different types of microbes with Plasmodium Falciparum. Environmental factors have been shown to be influential in the immune response of mosquitoes against the malaria-causing parasites.

Boisierre et al. study the effect of environmental factors, in tangent with natural mosquito immune response, against Plasmodium falciparum infections⁷. Their goal is to determine what impacts the success or lack thereof of parasite transmission by Anopheles gambiae. Through analysis of bacterial flora in the guts of Anopheles gambiae they show that the types of microbial life present are a result of the mosquito breeding sites. In addition, the presence of Enterobacteriaceae is highly correlated with the success of Plasmodium falciparum.

Dong et al. analyze infection rates of Plasmodium falciparum in the Anopheles gambiae, a type of mosquito well known for transmitting malaria⁸. Their goal is to better understand how microbial flora can regulate the development and transmission of malaria. They find that there are large differences between septic and aseptic mosquitos, because of the varying amounts of microbial flora that grows in their guts. The microbes help to create immune cells including anti-Plasmodium factors which may inhibit the development of Plasmodium falciparum.

Introduction of Bacteria to A. gambiae

The presence of Wolbachia within an insect cell is shown by a transmission electron micrograph. [4]

The Wolbachia pipientis bacteria, shown on the right, normally infect many arthropod species. Wolbachia pipientis bacteria do not infect Anopheles gambiae in nature. The bacteria were introduced experimentally to the Anopheles gambiae mosquitoes to test whether they could be used to control the spread P. falciparum. Experiments showed that virulent strains of the bacteria can survive and replicate when injected into a mosquito, demonstrating that viable infections are possible⁹. The result is hopeful, since the artificial infection of mosquitoes with the Wolbachia pipientis bacteria can negatively affect the development of malaria, as well as the mosquito population itself⁹. However, the use of Wolbachia pipientis to control P. falciparum is dependent on successful vertical transmission of Wolbachia pipientis in A. gambiae, which has yet to be tested.

Conclusion

Malaria is a persistent and dangerous infectious disease. By studying the most influential strain, Plasmodium falciparum, researchers have been able to better understand the mechanism of spread through Anopheles gambiae, and discover new possible approaches for malaria control.
More research is required to discover effective control methods that can be implemented on large populations, and prevent future malaria outbreaks.

References

1. Kaiser Family Foundation. "The Global Malaria Epidemic" Fact Sheet. November 2012.

2. Perlmann, P., and M. Troye-Blomberg. "Malaria blood-stage infection and its control by the immune system." Folia biologica 46.6 (2000): 210.

3. Gardner, Malcolm J., et al. "Genome sequence of the human malaria parasite Plasmodium falciparum." Nature 419.6906 (2002): 498-511.

4. Koella, Jacob C., Flemming L. SÖrensen, and R. A. Anderson. "The malaria parasite, Plasmodium falciparum, increases the frequency of multiple feeding of its mosquito vector, Anopheles gambiae." Proceedings of the Royal Society of London. Series B: Biological Sciences 265.1398 (1998): 763-768.

5. Tahar, Rachida, et al. "Immune response of Anopheles gambiae to the early sporogonic stages of the human malaria parasite Plasmodium falciparum." The EMBO journal 21.24 (2002): 6673-6680.

6. Meister, Stephan, et al. "Anopheles gambiae PGRPLC-mediated defense against bacteria modulates infections with malaria parasites." PLoS pathogens 5.8 (2009): e1000542.

7. Boissière, Anne, et al. "Midgut microbiota of the malaria mosquito vector Anopheles gambiae and interactions with Plasmodium falciparum infection." PLoS Pathogens 8.5 (2012): e1002742.

8. Dong, Yue mei, Fabio Manfredini, and George Dimopoulos. "Implication of the mosquito midgut microbiota in the defense against malaria parasites." PLoS pathogens 5.5 (2009): e1000423.

9. Jin, Chaoyang, Xiaoxia Ren, and Jason L. Rasgon. "The virulent Wolbachia strain wMelPop efficiently establishes somatic infections in the malaria vector Anopheles gambiae." Applied and environmental microbiology 75.10 (2009): 3373-3376.

10. Fang, Weiguo, et al. "Development of transgenic fungi that kill human malaria parasites in mosquitoes." Science 331.6020 (2011): 1074-1077.

11. "DPDx - Malaria Image Library"

Edited by Lydia de Pillis-Lindheim, a student of Nora Sullivan in BIOL187S (Microbial Life) in The Keck Science Department of the Claremont Colleges Spring 2013.