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.

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 left) is one of the most efficient malaria vectors known because it transmits Plasmodium falciparum².

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]

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 right, occurs as follows¹¹:

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. 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.

Lifecycle of Malaria. [2]

The reason for the difficulty in immunizing people against malaria is found in the sequencing of Plasmodium Falciparum genome. Gardner et al. analyzed the sequences in 2002, and compared the Plasmodium Falciparum genome to those of other free-living eukaryotic microbes. They found that the genome encodes fewer enzymes and transporters, but that it encodes a high proportion of genes dedicated to evading immune responses and host-parasite interactions ³.

This bloodsmear of a P.falciparum culture (K1 strain) shows the presence of malaria in its ring stages: schizont in the lower center, and trophozoite on the left.

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 its primary vector.

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.

There are drugs which have been used to effectively treat the illness, after an infection has already occured. These include chloroquine, primaquine, and artemisinin-based combination therapy (ACT)^2.

Since is not possible to simply immunize at-risk individuals, the focus of malaria prevention is on reducing or controlling the spread of the disease. More specifically, studies on the microbial interactions of Plasmodium falciparum and the vector which spreads it, Anopheles gambiae, are able to shed some light on possible approaches for malaria control.

Regulation Through Anopheles Gambiae Immune Response

One approach to malaria control that has been studied has been that of using the mosquito immune response as a defense mechanism against malaria. An understanding of the immune system itself is a key step in this approach. When Plasmodium falciparum enters a mosquito, there is a systematic immune response⁵. The presence of P. falciparum gametocytes in the mosquito gut regulates the amount of gene expression occuring in mosquito guts⁵.

"This photomicrograph of a blood smear contains a macro- and microgametocyte of the Plasmodium falciparum parasite. Both macro- and microgametocytes are products of the erythrocytic life cycle. Within a few minutes after the Anopheles sp. vector ingests the gametocytes, microgametocytes develop into microgametes, which are able to fertilize gametes."

Meister et al. study the structure and function of transmembrane PGN Recognition Protein LC, which is a receptor of a signaling pathway which affects the proliferation of microbes in mosquito guts⁶. Their goal is to show how the PGRP-LC can regulate immune responses of mosquitoes against both Plasmodium falciparum, which infects humans, and Plasmodium berghei, which can infect rodents. They demonstrate that the connection between the defense mechanism regulated by PGRP-LC and the bacterial communities in mosquitoes can be used to control malaria transmission.

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.

Regulation By Introduction of New Bacteria

A different approach to controlling the P. falciparum population is by the introduction of a new bacteria to Anopheles gambiae.

In a study in 2009, Jin et al. seek a viable approach to malaria control, and do so by focusing on the Wolbachia pipientis bacteria, which can affect the development of malaria, as well as affect the mosquito population itself⁹. The Wolbachia pipientis bacteria, shown on the right, do not infect Anopheles gambiae in nature. The authors introduce the bacteria experimentally to the Anopheles gambiae mosquitoes. They find that virulent strains of the bacteria can survive and replicate when injected into a mosquito, demonstrating that viable infections are possible.

"Transmission electron micrograph of Wolbachia within an insect cell."

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.

"As a protist, the plasmodium is a eukaryote of the phylum Apicomplexa. Unusual characteristics of this organism in comparison to general eukaryotes include the rhoptry, micronemes, and polar rings near the apical end. The plasmodium is known best for the infection it causes, malaria."

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.